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Potential of Tumor Necrosis Factor Inhibitors in Psoriasis and Psoriatic Arthritis
Abstract
To summarize the role of tumor necrosis factor (TNF) in the pathogenesis of psoriasis and psoriatic arthritis (PsA) and to present the latest data on the efficacy of TNF inhibitors in these diseases.
PubMed was used with the following indexing terms: TNF, TNF inhibitor, psoriasis, psoriatic arthritis, etanercept, infliximab, and/or T cell. Abstract booklets and manufacturer's package inserts were also used. When possible, only sources published after the year 2000 were incorporated.
Sources that described a role for TNF in the pathogenesis of psoriasis and PsA were selected based on relevance. Clinical trials that examined the efficacy of the TNF inhibitors etanercept and infliximab in psoriasis and PsA were selected.
Data were extracted if they represented safety information, the American College of Rheumatology criteria for improvement, the Health Assessment Questionnaire, or the PsA response criteria. These data were abstracted independently by the authors.
Aberrant regulation of TNF is involved in the development of psoriasis and PsA. Therefore, recent intervention strategies for psoriasis and PsA have incorporated biologic agents that specifically target TNF. Etanercept and infliximab are effective at reducing disease activity and are generally well tolerated in the treatment of psoriasis and PsA.
Tumor necrosis factor plays a major role in the pathogenesis of psoriasis and PsA, and TNF antagonists provide clinicians with a worthy alternative to traditional therapies, which are associated with toxic effects and poor compliance.
... Tumor necrosis factor alpha (TNF-α) is a master cytokine in the pathogenesis of psoriasis. By binding to its specific p55 and p75 receptors, it triggers an inflammatory cytokine cascade that inhibits keratinocyte apoptosis, induces keratinocyte hyperproliferation in the skin, and causes inflammation and destruction in the joints [1]. TNF-α levels are elevated in psoriatic plaques, serum, and synovial fluid of patients with psoriasis and the levels correlate positively with disease severity [1][2][3]. ...
... By binding to its specific p55 and p75 receptors, it triggers an inflammatory cytokine cascade that inhibits keratinocyte apoptosis, induces keratinocyte hyperproliferation in the skin, and causes inflammation and destruction in the joints [1]. TNF-α levels are elevated in psoriatic plaques, serum, and synovial fluid of patients with psoriasis and the levels correlate positively with disease severity [1][2][3]. Under physiological conditions, TNF-α plays a crucial role in the formation and maintenance of granulomas that contain mycobacterial infections, which cannot otherwise be eradicated by the host defence mechanisms [4]. ...
Tumor necrosis factor (TNF) plays an important role in containing mycobacterial infections. With the rapidly increasing role of TNF inhibitors in dermatology, tuberculosis (TB) is becoming an important and worrisome concern to dermatologists. This paper aims to provide a comprehensive review on the incidence of TB in patients treated with anti-TNF, the variety of TB screening methods, and management of these cases. Various national recommendations have been highlighted. The monoclonal antibodies, infliximab and adalimumab, appear to be more associated with the risk of TB reactivation than the soluble receptor etanercept. Tuberculosis associated with TNF inhibitors, in contrast to classical TB, is more likely to be disseminated, atypical, extra pulmonary, and life threatening. Vigilance for typical and atypical presentations of active TB is mandatory until the end of therapy. Although tuberculin standard test (TST) has been the gold standard for screening of latent TB infection (LTBI) for close to a century, it has several inadequacies and may be unreliable in patients with widespread psoriasis. Interferon gamma release assays (IGRAs) with better diagnostic specificity and sensitivity are a promising adjunct to diagnose LTBI at present. Although appropriate screening and treatment of LTBI will lower the risk of reactivation to a great extent, no chemoprophylactic regimen is fully protective.
... Therapeutic approaches based on anti-TNF-α agents have provided indirect evidence in support to this hypothesis, since they are highly effective in controlling both skin and joint manifestations in patients with PsA (Schopf et al., 2002& Galadari et al., 2003. Gottlieb (2003), Krueger and Callis (2004) and Mastroianni et al. (2005) demonstrated that the marked improvement in both skin and joint manifestations following therapy with Infliximab, a chimeric monoclonal antibody which binds specifically to human TNF-α, was significantly associated to the decrease of serum levels of TNF-α, angiogenic molecules and MMP-2. Some data from large placebocontrolled studies have shown that the medication is highly effective (Gottlieb et al., 2004& Antoni et al., 2005. ...
... However, there was no increase in the expression of Th2 cytokines (IL-4, IL-5, and IL-10) in tissues/cells dysregulated by disease. It should be noted that the proliferation of keratinocytes is not induced by IFN-γ or TNF-α [7]. Results of previous genetic studies have steered the attention to IL-23/Th17 function, which is involved in controlling of proinflammatory process in psoriatic plaques which involves keratinocytes, dendritic cells, and T cells [8]. ...
Psoriasis is the most common, inflammatory, chronic skin disease, with possible systemic manifestations. It affects about 2-3% of the population and is equally common in women and men. Many factors, such as environmental, hormonal, genetic and immunological, play a role in the development of psoriasis. Interleukin 22 and 23 (IL-22, IL-23) as well as tumor necrosis factor alpha (TNF-α) play an important role in the pathogenesis of this disease. The cause of psoriatic lesions is uncontrolled excessive proliferation of the epidermis, accompanied by parakeratosis and increased expression of transforming growth factor α (TGF-α), a ligand of the epidermal growth factor receptor (EGF).
The treatment choice for psoriasis depends on the severity of the disease as assessed on available scales. In the first place, topical medications are used to treat this disease. More advanced external treatments include phototherapy (ultraviolet radiation type B - UVB) or psoralen plus ultraviolet radiation type A (UVA). A patient with severe psoriasis can be treated with systemic medications such as methotrexate, cyclosporine, acitretin, and biological drugs.
The decision to use biologics should be carefully considered, based on the clinic and the patient's individual risk profile. The types of biological drugs for the treatment of psoriasis are selected depending on the severity of the disease and comorbidities. The main indication for biological treatment is moderate to severe psoriasis.
Groups of biological drugs have been distinguished on the basis of their mechanisms of action. These are: tumor necrosis factor α (Tumor Necrosis Factor-α TNF-α) inhibitors, IL-17 / IL-23 p40 inhibitors, IL-17A inhibitors, IL-17 receptor A, IL-23 p19. The studies conducted so far indicate the well-documented safety and tolerability of biological drugs used in psoriasis.
Biological therapy, despite the possibility of side effects, is considered a safe, well-tolerated and the preferred therapeutic method, especially in patients with moderate to severe psoriasis.
... уровень фНО-α повышен в псориатических бляшках, сыворотке крови и синовиальной оболочке при псориатическом артрите. уровень фНО-α коррелирует с активностью псориаза [12,13]. ...
The article systematizes information about genetic polymorphisms associated with the risk of psoriasis and psoriatic arthritis development. Gene variants that are potentially essential for their inclusion in genetic tests were sampled taking into consideration polymorphism localization. The presented data are sufficient to prepare the genetic profile of psoriatic patients, forecast the clinical course of the disease and potential efficacy of treatment, and calculate the risk of the disease development in the patients relatives.
... Авторы отмечают, что наиболее выраженное повышение концентрации этого цитокина наблюдалось у больных с распространенными высыпаниями и тяжелыми клиническими формами, плохо поддающимися терапии [28]. повышенный уровень фНО-α обнаружен также в синовиальной жидкости и в синовиальной оболочке больных псориатическим артритом [29,30]. ...
The article presents the authors data related to an ongoing study of the expression of pro-inflammatory IL-1 and TNF alpha cytokines in affected skin foci in psoriatic patients. The authors revealed particular features related to the increased expression of IL-1 in the skin structures with absence of TNF alpha expression.
... Самым ранним событием в развитии псориаза является приток активированных cd4+ клеток, которые индуцируют иммунные реакции, в том числе активацию макрофагов, синтезирующих широкий спектр провоспалительных медиаторов, в первую очередь фактор некроза опухоли-α [1]. Он в свою очередь запускает цитокиновый каскад, стимулирующий кле-точную активность эпидермиса, благодаря которой формируются эпидермальная гиперплазия, акантоз, эритема, клинически проявляющиеся формированием псориатических папул и бляшек [2]. ...
Topical glucocorticosteroids rank first among drugs for the external therapy of psoriasis. When selecting a drug, it is necessary to take into account the disease sensitivity to different classes of topical steroids. Dermovate (clobetasol propionate) is the most efficient drug for the external therapy of moderate to severe psoriasis. When this drug was used as a part of the complex treatment of psoriasis, regression of eruptions was observed within three weeks in 97.4% of patients, and in 91.5% of patients if the process was localized in the area of palms and soles. Major indications for its use are torpidity with regard to the previous therapy, localization in the field of palms and soles, and substantial reduction in the life quality.
... Therefore, Th1 cells have been the predominant focus of psoriasis research. However, administration of IFN-γ and TNF-α does not reproduce psoriasis pathology [7][8][9], suggesting that Th1 cell induction of experimental psoriasis cannot be fully explained by Th1 cytokine function. ...
Psoriasis is a chronic inflammatory skin condition caused by a combination of hereditary and environmental factors. Its development is closely related to the adaptive immune response. T helper 17 cells are major IL-17-producing cells, a function that plays an important role in the pathogenesis of psoriasis. However, recent findings have demonstrated that innate immune cells also contribute to the development of psoriasis. Innate lymphoid cells, γδ T cells, natural killer T cells, and natural killer cells are activated in psoriasis, contributing to disease pathology through IL-17-dependent and -independent mechanisms. The present review provides an overview of recent findings, demonstrating a role for innate immunity in psoriasis.
... Methotrexate, cyclosporine and acitretin have potent immunosuppressive effects and are indicated only for patients with severe psoriasis (11). More recently, the use of biological pharmaceuticals has increased for the treatment of psoriasis; adalimumab, infliximab, certolizumab and golimumab are antibodies that block the effect of TnFα, while etanercept is an antibody that contains a portion of the TnFα receptor (12). Ustekinumab and briakinumab are also antibodies used in the treatment of psoriasis with specificity to protein-40, a common component of il-12 and il-23, which are involved in the differentiation of Th1 and Th17 cells, respectively (13,14). ...
During the progression of psoriatic lesions, abundant cellular infiltration of myeloid cells, such as macrophages and activated dendritic cells, occurs in the skin and the infiltrating cells interact with naive lymphoid cells to generate a T helper (Th)1 and Th17 environment. Therapies to treat psoriasis include phototherapy, non‑steroidal and steroidal drugs, as well as antibodies to block tumor necrosis factor‑α, interleukin (IL)‑17‑A and IL‑12/IL‑23, which all focus on decreasing the proinflammatory hallmark of psoriasis. The present study obtained the heptapeptide HP3 derived from phage display technology that blocks mononuclear cell adhesion to endothelial cells and inhibits trans‑endothelial migration in vitro. The activity of the heptapeptide in a murine model of psoriasis was also assessed, which indicated that early administration inhibited the development of psoriatic lesions. Therefore, the results suggested that HP3 may serve as a potential therapeutic target for psoriasis.
... TNF-α and IFN-γ are characteristic cytokines for Th1 lymphocytes, whereas IL17 and TGFβ are characteristic for the Th17 lymphocyte phenotype (Sakkas & Bogdanos, 2017;Schurich, Raine, Morris, & Ciurtin, 2017). Therefore, it seems reasonable to conclude about the complex immunogenicity of psoriasis and considering that TNF-α and IFN-γ do not induce the proliferation of keratinocytes (Hancock, Kaplan, & Cohn, 1988;Krueger, & Callis, 2004), as a role for different lymphocyte subpopulations. ...
Introduction:
Molecular analysis is key to a better understanding of drug resistance during therapy.
Aim:
The aim of this study was to evaluate changes in the expression of tumor necrosis factor α (TNF-α), interleukin (IL) - IL12A, IL12B, IL23A, interferon gamma (IFN-γ) in psoriatic patients during 84 days of treatment and TNF-α on the protein level.
Material and methods:
The study group consisted of 32 psoriatic patients during cyclosporine A therapy. The molecular analysis was made by using real-time reverse transcription polymerase chain assay (RTqPCR) and MALDI ToF mass spectroscopy three times: after 0, 42, 84 days of treatment.
Results:
Statistically significant differences (p<0.05) in transcriptional activity were observed for genes: TNF-α (0 vs 42nd days p=0.006; 0 vs 84th days p=0.005), IL23A (0 vs 42nd days p=0.041), IFN-γ (0 vs 42th days p=0.040; 0 vs 84th days p=0.041), IL17 (0 vs 42nd p=0.000003 0 vs 84th p=0.001650), IL12A (0 vs 42nd p=0.0047vs 84th p=0.0063). The expression of TNF-α was downregulated during therapy, IL23A was upregulated during CsA treatment, while the expression of IFN-γ and IL17 were higher after 42 days and lower after 84 days compared to 0 days of CsA treatment.
Conclusions:
It seems that TNF-α, IL12A, IL23A, IFN-γ and IL17 can be useful complementary molecular markers to assess the efficacy of psoriasis treatment. This article is protected by copyright. All rights reserved.
... The importance of the proinflammatory molecule TNF-α in psoriatic skin has already been known for a long time [25][26][27]. Produced by a variety of skin cells including T-cells, macrophages, DC and keratinocytes, the most prominent effect of TNF-α in psoriasis might be the upregulation of IL-23. ...
Psoriasis is a chronic skin disorder driven by IL-23 and the downstream T-helper cell 17 (Th17) pathway. Tildrakizumab is a humanized monoclonal antibody selectively targeting the p19 subunit of IL-23, a key cytokine for Th17 cells. Here, we provide an overview of IL-23 in the context of psoriasis pathogenesis and review the results of the Phase I, II and III clinical trials for tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis in order to assess its efficacy, safety and clinical usefulness. In all clinical trials, tildrakizumab demonstrated significant clinical improvement and a favorable safety profile. In Phase III trials, 75% of tildrakizumab-treated patients reached a Psoriasis Area and Severity Index 75 at week 28 demonstrating superior efficacy as compared with etanercept treatment. The tildrakizumab-induced reduction in skin inflammation proves the important pathogenic role of IL-23 in psoriasis and further supports the utility of drugs targeting the IL-23/Th17 pathway. Targeting IL-23p19 with tildrakizumab augments the therapeutic repertoire for patients with moderate-to-severe chronic plaque psoriasis.
... Also, it could increase mitogen proliferation and Ig secretion, causing excessive keratinocytes proliferation and differ-entiation [30][31][32][33][34] . Therefore, TNFi treatment focus on inhibiting TNF expression, decreasing inflammatory cytokines activation and suppressing keratinocytes proliferation, thereby blocking inflammation and contributing on remission of skin lesions in psoriasis patients 6,[35][36][37] . These could be used to explain the findings in present study; after TNFi treatment, high effects on PASI75 of 58.3% and PASI90 of 43.1% at M6 were observed. ...
Objective:
This study aimed to investigate the correlation of serum calprotectin expression with risk and severity of psoriasis, as well as its predictive value for clinical response to tumor necrosis factor inhibitors (TNFi) treatment in psoriasis patients.
Patients and methods:
72 psoriasis patients and 70 health controls (HCs) were enrolled. Blood samples were collected, and serum calprotectin was determined by commercial enzyme-linked immuno sorbent assay (ELISA). All patients were treated by TNFi treatment, and followed up at 6 months, and the last follow-up date was 2016/11.
Results:
Calprotectin level was elevated in psoriasis patients compared to HCs (p < 0.001), and it disclosed a good diagnostic value of psoriasis with area under curve (AUC) 0.872, 95% CI: 0.810-0.935. Calprotectin expression was positively associated with Psoriasis Area and Severity Index (PASI) score (R = 0.452, p < 0.001), while it was not associated with BSA (R = 0.125, p = 0.297). 58.3% patients achieved PASI75 and 43.1% patients achieved PASI90 at M6. Calprotectin was decreased during the 6-month treatment (p < 0.001). Changes of calprotectin during the first month (∆calprotectin (M0-M1)) in PASI75 group were more than that of non-PASI75 group (p < 0.001). Also, multivariate logistic analysis revealed that ∆calprotectin (M0-M1) (p = 0.001) was an independent factor for PASI75 achievement at M6 after TNFi treatment, while pre-systemic biologic treatment (p = 0.001) was an independent factor for non-PASI75 achievement.
Conclusions:
Serum calprotectin expression is correlated with risk and severity of psoriasis, and the decrease of calprotectin during the first month could predict better clinical response to TNFi treatment in psoriasis patients.
... Anti-TNF-α agents have been shown to be effective in treating immune-mediated inflammatory disorders such as rheumatoid arthritis (RA), Crohn's disease (CD), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and moderate to severe plaque psoriasis. 1 Anti-TNF-α agents such as adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), are biologic agents used for targeted therapy, which act to block the cytokine TNF-α, thereby inhibiting this cytokine's systemic effects. These are thought to have significantly less major organ toxicity when compared with pre-biologic agents such as methotrexate and cyclosporine. ...
Background
The anti-TNF-α agents adalimumab, infliximab and etanercept are indicated for a variety of autoimmune diseases such as rheumatoid arthritis (RA), Crohn's disease (CD), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and psoriasis (Pso). In some patients treated for nonpsoriatic conditions such as rheumatoid arthritis and Crohn's disease, these agents have been associated with the appearance of psoriasis (either its emergence or exacerbation)—a term previously coined TNF-α antagonist induced psoriasis.
Objective
This article reviews published data demonstrating this phenomenon.
Methods
Studies with English abstracts between 2000–2008, identified in MEDLINE and PUBMED with keywords anti-TNF, psoriasis, TNF-α antagonist and induced, were retrospectively reviewed.
Results
An association between use of anti-TNF agents and the appearance of psoriasis was seen in a total of 219 patients from 38 reports.
Conclusion
There is an association between use of anti-TNF agents and appearance of psoriasis, but the specific nature of the relationship is unknown. Recent studies help to delineate patient characteristics common among the group, as well as theorize proposed mechanisms for the emergence of psoriasis. At this time, however, further investigation into this multi-factorial condition is needed.
... However, keratinocyte proliferation is not induced by IFN-c or TNF-a, either. [13][14][15] The pathogenesis of psoriasis could not be fully understood based only on Th1 functions, and it was predicted that other key players should participate in its occurrence. ...
The pathogenesis of psoriasis can be explained by dysregulation of immunological cell function as well as keratinocyte proliferation/differentiation. Recently, the immunological pathomechanism has been clarified substantially. Whereas T-helper (Th)1 overactivation was thought to induce occurrence of psoriasis, it has been demonstrated that Th17 cells play a key role. Th17 development is maintained by interleukin (IL)-23 mainly produced by dendritic cells. Th17 cells produce various cytokines, including IL-17A, IL-17F and IL-22. IL-17A and IL-22 induce not only keratinocyte proliferation, but also tumor necrosis factor (TNF)-α, chemokine (C-X-C motif) ligand (CXCL)1 and CXCL8 production. TNF-α accelerates the infiltration of inflammatory cells, including lymphocytes, monocytes and neutrophils, from the peripheral blood into skin with dendritic cell activation. In addition, antimicrobial peptides are overexpressed in psoriatic skin lesions, and the antimicrobial peptide, LL-37, activates dendritic cells, which leads to the development of inflammation. Furthermore, activation of nuclear factor-κB signal induces the expression of keratins 6 and 16 in keratinocytes, which are associated with acanthosis and reduced turnover time in the epidermis. The progression of the pathomechanism contributes to the development of new therapies for psoriasis.
... TNFα mediates keratinocyte proliferation, cell adhesion, and trafficking to lesional sites, and stimulates growth and invasiveness of dermal fibroblasts. [2][3][4][5] The TNFα antagonist infliximab is a murine-human chimeric monoclonal antibody constructed from murine and human DNA sequences comprising a mouse variable region and a human immunoglobulin G1-α constant region. Infliximab neutralizes the biologic activity of TNFα by binding with high affinity to the soluble and membranebound TNFα forms, thereby inhibiting binding of TNFα with its receptors, 4 and has been shown to be highly effective for the treatment of psoriasis, producing rapid and dramatic decreases in epidermal inflammation and normalization of keratinocyte differentiation in psoriatic plaques that precede maximal clinical response. ...
Caterina Fabroni,1 Angelo Massimiliano D’Erme,2 Torello Lotti3 1Department of Dermatology, Misericordia e Dolce Hospital, Prato, Italy; 2Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy; 3Guglielmo Marconi University, Rome, Italy Abstract: Psoriasis is an inflammatory dermatologic disease that can often involve not only the skin and mucosal surfaces but also the bones and joints. It affects approximately 3% of the world’s population, and has a chronic-relapsing course. The management of psoriasis is often difficult and, particularly in the case of moderate to severe forms, the use of systemic therapies is mandatory. The introduction of biologic drugs has greatly improved our ability to treat psoriasis. However, it is necessary to underline that antitumor necrosis factor-α treatments may reactivate latent tuberculosis infection and cause particularly disseminated or extrapulmonary disease. Physicians should carry out proper screening of patients before starting treatment with antitumor necrosis factor-α, in order to identify individuals with latent tuberculosis infection. We report our experience in this field and review the various existing tests to screen for tuberculosis. Keywords: infliximab, adalimumab, tuberculosis, psoriasis
... TNF can also activate endothelial cells (15), potentiate differentiation of monocytes into osteoclasts (16), and induce release of matrix metalloproteinases by synovial fibroblast cells (17). The recognition that TNF has a pivotal role in inflammation and is present at elevated concentrations in psoriasis and PsA led to controlled clinical trials in which it was demonstrated that the TNF antagonists etanercept and infliximab had efficacy in both psoriasis and PsA (18)(19)(20)(21)(22). TNF has thus been validated as an appropriate therapeutic target in these diseases (23). ...
... It plays a major role in tissue inflammation [14] and remodeling [15] by stimulating the production of collagenase. Particularly, TNF-α can activate the production of other proinflammatory cytokines, up-regulate some transcription factors and promote keratinocytes proliferation, which may lead to pathological inflammation in several organs, such as skin and joints [16,17]. IL-1β and TNF-α, as the well-known proinflammatory cytokines, could be treated as the mediators of shock [18][19][20][21], also present at high concentrations in bronchoalveolar lavage fluid of patients with sustained ARDS [20]. ...
Ple iotropic proinflammatory cytokines, interleukin- 1 (IL-1) and tumor necrosis factor-α (TNF-α), involved in the regulations of various immune responses, inflammatory processes and hematopoiesis. In the present study, the expression levels of IL-1 and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA). Following the cytokine blockade as a successful clinical therapy for autoimm une diseases such as rheumatoid arthritis, the patients are more susceptible to a variety of opportunistic infections. IL-1 and TNF-α may be useful predictive biomarkers of diseases and offer potential targets for therapeutic intervention of inflammatory diseases. However, our results showed that the plasma IL-1 level was significantly higher in women compared to men (69.5 ± 19.8 pg/ ml in men and 80.1 ± 19.5 pg/ml in women, respectively); the plasma levels of TNF-α were higher in men than women (20.8 ± 4.9 pg/ml and 18.7 ± 7.1 pg/ml, respectively). The significant gender difference of plasma interleukin-1 (IL-1) and TNF-α levels present in healthy adults in Jiangsu Province, China (P=0.002 and P=0.015, respectively), and may be as a hint for sex differences of susceptibility to many diseases and elementary immune response.
... It has a diverse set of functions, including effects on inflammation, cell propagation, differentiation, death and immune regulation [6,7]. Imbalance of TNF-can induce many pathological conflicts such as autoimmune, chronic inflammatory and infectious diseases as well as solid tumors [8][9][10][11], therefore inhibition of TNF-is considered as an effective treatment modality [12]. ...
The antibody display technology (ADT) such as phage display (PD) has substantially improved the production of monoclonal antibodies (mAbs) and Ab fragments through bypassing of several limitations associated with the traditional approach of hybridoma technology. In the current study, we capitalized on the PD technology to produce high affinity single chain variable fragment (scFv) against tumor necrosis factor-alpha (TNF-α), which is a potent pro-inflammatory cytokine and play rules in various inflammatory diseases and malignancies. To pursue production of scFv antibody fragments against human TNF-α, we performed five rounds of biopanning using stepwise decreased amount of TNF-α (1 to 0.1 μg), a semi-synthetic phage antibody library (Tomlinson I + J) and TG1 cells. Antibody clones were isolated and selected through enzyme-linked immunosorbent assay (ELISA) screening. The selected scFv antibody fragments were further characterized by means of ELISA, PCR, restriction fragment length polymorphism (RFLP) and Western blot analyses as well as fluorescence microscopy and flow cytometry. Based upon binding affinity to TNF-α, 15 clones were selected out of 50 positive clones enriched from PD in vitro selection. The selected scFvs displayed high specificity and binding affinity with Kd values at nm range to human TNF-α. The immunofluorescence analysis revealed significant binding of the selected scFv antibody fragments to the Raji B lymphoblasts. The effectiveness of the selected scFv fragments were further validated by flow cytometry analysis in the lipopolysaccharide (LPS) treated mouse fibroblast L929 cells. Based upon these findings, we propose the selected fully human anti-TNF-α scFv antibody fragments as potential immunotherapy agents that may be translated into preclinical/clinical applications.
... Because EC-SOD is downregulated by TNF-a (Stralin and Marklund, 2000), and TNF-a is highly expressed in psoriatic lesions, it is possible that the lower level of EC-SOD in psoriasis is due to increased TNF-a production. The TNF-a inhibitors, infliximab and etanercept, are effective for the treatment of psoriasis (Krueger and Callis, 2004). In addition, it was reported that infliximab protected EC-SOD from decreased expression of EC-SOD by TNF-a in vitro (Adachi et al., 2006). ...
Psoriasis is a common chronic and complex autoimmune inflammatory skin disorder. The histological characteristics of psoriasis are epidermal hyperplasia, mononuclear leukocyte infiltration into the dermis, and increased angiogenesis. However, the mechanisms involved in the pathogenesis of psoriasis remain unclear. Extracellular superoxide dismutase (EC-SOD) has antichemotactic activities. Because immune cell infiltration is seen in psoriatic lesions and psoriasis patients express low levels of EC-SOD, we hypothesized that the lack of EC-SOD induces more severe IL-23-mediated psoriasis-like skin inflammation. To test this hypothesis, we determined whether the loss of EC-SOD causes more severe IL-23-induced skin inflammation. Ear skin after IL-23 administration was thicker in EC-SOD knockout (KO) mice compared with wild-type mice. In addition, infiltration of CD4(+) T cells, macrophages, and dendritic cells (DCs) into IL-23 injection sites was more elevated in EC-SOD KO mice. The expression of proinflammatory cytokines and chemokines was also more elevated in EC-SOD KO mice, and EC-SOD KO DCs expressed a higher level of MHCII. Finally, EC-SOD transgenic mice showed much less severe IL-23-induced skin inflammation. Therefore, EC-SOD may inhibit IL-23-induced psoriasis-like inflammation through the inhibition of immune cell infiltration and immune responses. These results suggest that EC-SOD could be a possible candidate for management of psoriasis.Journal of Investigative Dermatology advance online publication, 6 December 2012; doi:10.1038/jid.2012.406.
... Biological therapy based on monoclonal antibodies against TNF-α has been proven to be effective in patients with psoriatic arthritis on both the arthropaty and the cutaneous symptoms of the disease[15,16,28]. Today there are three main biological agents targeting TNF-α, which are already in use for treating PsA. ...
Inflammation represents an early and key event in the development of both the cutaneous psoriasis and psoriatic arthritis. Compelling evidences indicate that the production of TNF-alpha plays a central role in psoriasis by sustaining the inflammatory process in the skin as well as in the joints. Among the multiple effects produced by TNF-alpha on keratinocytes, the induction of matrix metalloproteinase-9 (MMP-9), a collagenase implicated in joint inflammatory arthritis which acts as an angiogenesis promoting factor, might represent a key mechanism in the pathogenesis of the disease. Aims of the present study were to investigate a) the role of MMP-9 in the development of psoriasis by assessing the presence of MMP-9 in lesional skin and in sera of psoriatic patients; b) the association of MMP-9 with the activity of the disease; c) the relationship between MMP-9 and TNF-alpha production.
Eleven psoriatic patients, clinically presenting joint symptoms associated to the cutaneous disease, were included in a therapeutic protocol based on the administration of anti-TNF-alpha monoclonal antibody (Infliximab). Sera and skin biopsies were collected before treatment and after 6 weeks of therapy. Tissues were kept in short term cultures and production soluble mediators such as TNF-alpha, MMP-9, MMP-2, VEGF and E-Selectin, which include angiogenic molecules associated to the development of plaque psoriasis, were measured in the culture supernatants by immunoenzymatic assays (ng/ml or pg/ml per mg of tissue). MMP-9 concentrations were also measured in the sera. The cutaneous activity of disease was evaluated by the Psoriasis Area and Severity Index (PASI).
Clinical and laboratory assessment indicated that all but one patients had a significant improvement of the PASI score after three months of therapy. The clinical amelioration was associated to a significant decrease of MMP-9 (P = 0.017), TNF-alpha (P = 0.005) and E-selectin (P = 0.018) levels, spontaneously released by lesional biopsies before and after therapy. In addition, significant correlations were found between the PASI measurements and TNF-alpha (r2 = 0.33, P = 0.005), MMP-9 (r2 = 0.25, P = 0.017), E-selectin (r2 = 0.24, P = 0.018) production. MMP-9 levels were significantly correlated with those of TNF-alpha (r2 = 0.30, P = 0.008). A significant decrease of MMP-9 in the sera, associated to the clinical improvement was also found.
Our findings show the existence of a direct relationship between MMP-9 and TNF-alpha production strongly suggesting that MMP-9 may play a key role in the skin inflammatory process in psoriasis.
... Etanercept, infliximab, and adalimumab are inhibitors of the proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣ ). Alefacept and efalizumab block T cell activities: alefacept by inducing a selective depletion of CD45RO+ memory effector T cells through apoptotic cell death, and efalizumab by reversibly modulating various T cell functions, including activation and trafficking, without depleting T cells [5][6][7][8][9][10][11] . ...
In February 19, 2009, the European Medicines Agency (EMA) had recommended the suspension of the marketing authorization for efalizumab after the occurrence of cases of progressive multifocal leukoencephalopathy.
To explore the efficacy of alternative therapies for psoriasis and the health status of patients who discontinued efalizumab.
An observational study was performed on 101 patients. After the EMA communication, efalizumab was discontinued in the following 2-3 months. In agreement with the patients, we decided to either prescribe other treatments or none at all.
After 1 year, 11 patients are still not treated, 63 patients are treated with biologics, and 9 patients are treated with systemic conventional therapies.
In order to prevent rebound or relapse, various approaches are available, including cyclosporine, methotrexate and biologic therapies. Interestingly, in 11 out of 31 patients who did not receive any systemic drug, psoriasis is still under control, suggesting a long-term effect of efalizumab.
... Several of these genes are strong functional candidates. For instance, MICA and MICB are nonclassical MHC genes that participate in the regulation of CD8+ T-cells and NK cells (58), and the tumor necrosis factor and lymphotoxin genes encode proteins whose blockade is highly therapeutically effective (59). While our earlier studies of recombinant ancestral haplotypes argue strongly against a primary role for MHC Class III genes as the drivers of the HLA-Cw6 association signal (6,60), no comparable mapping studies exist as yet for the HLA-Cw1-B46 disease association in Asians. ...
Earlier studies have shown that psoriasis in Japan and Thailand is associated with two different major histocompatibility complex (MHC) haplotypes - those bearing HLA-Cw6 and those bearing HLA-Cw1 and HLA-B46. In an independent case-control sample from Thailand, we confirmed the association of psoriasis with both haplotypes. No association was seen in Thai HLA-Cw1 haplotypes lacking HLA-B46, nor was HLA-Cw1 associated with psoriasis in a large Caucasian sample. To assess whether these risk haplotypes share a common origin, we sequenced genomic DNA from a Thai HLA-Cw1-B46 homozygote across the ∼300 kb MHC risk interval, and compared it with sequence of a HLA-Cw6-B57 risk haplotype. Three small regions of homology were found, but these regions share equivalent sequence similarity with one or more clearly non-risk haplotypes, and they contain no polymorphism alleles unique to all risk haplotypes. Differences in psoriasis phenotype were also observed, including lower risk of disease, greater nail involvement, and later age at onset in HLA-Cw1-B46 carriers compared with HLA-Cw6 carriers. These findings suggest locus heterogeneity at PSORS1 (psoriasis susceptibility 1), the major psoriasis susceptibility locus in the MHC, with HLA-Cw6 imparting risk in both Caucasians and Asians, and an allele other than HLA-Cw1 on the HLA-Cw1-B46 haplotype acting as an additional risk variant in East Asians.
... In studies using animal models, the epidermal-specific expression of integrin b1 [10], TGF-b [11], Stat3 [12] or VEGF [13] causes epidermal hyperplasia which mimics psoriatic skin. In contrast, evidence that psoriasis is improved by bone marrow transplantation [14] or by new biologics, such as antibodies to TNF-a [15] or the IL-12/IL-23 p40 subunit [16], suggests the importance of immunological abnormalities in the disorder accompanied by the activation of Th1 cells [17], Th17 cells [18] and/or CD11c-positive dendritic cells (Tip-DC in mice) [19]. However, it has not been delineated whether the activation of signal transduction systems that regulate keratinocyte proliferation is involved in the induction of the cutaneous inflammation and/or its exacerbation in psoriasis, or in turn, whether the inflammatory reactions affect the progression of epidermal hyperplasia in psoriasis. ...
Raf is one of the downstream effectors of Ras GTPases. The induction of Raf in the epidermis causes the proliferation of keratinocytes and epidermal hyperplasia. However, skin inflammation accompanying Ras-induced epidermal reactions has not been fully delineated.
The aim of this study was to characterize inflammatory reactions induced by epidermal-specific Raf expression and to elucidate its role in skin inflammation.
K14-Raf:ER transgenic mice, in which the 4-hydroxytamoxifen (4OHT)-responsive mutant estrogen receptor (ER) ligand binding domain-Raf fusion gene was expressed under control of the keratin 14 promoter, were used to characterize inflammatory reactions induced by Raf expression in the epidermis.
A single topical application of 4OHT induced the expression of phosphorylated extracellular signal-related kinase 1/2 and elicited neutrophil-dominant inflammatory infiltrates in the skin. The Raf expression also rapidly induced the production of several cytokines and chemokines, including VEGF and CXCL1, by keratinocytes and inmouse skin in vivo. Furthermore, CD4-positive cells from regional lymph nodes had the potential to differentiate into IFNg- and IL17-producing cells. Treatment with an anti-Gr-1 antibody diminished the Raf-induced cutaneous inflammation and partially reversed the epidermal hyperplasia and hyperkeratosis.
Activation of the Raf signaling pathway is involved in the epidermal hyperplasia and the neutrophil-dominant cutaneous inflammatory reactions which are characteristics of psoriasis.
A common skin disorder called psoriasis causes thickened patches of the skin. Typically, it is discovered to be covered with silvery scales. Although psoriasis is regarded as a skin condition, it is actually the outcome of an immune system dysfunction. Types of psoriasis-Plaque psoriasis (psoriasis vulgaris), Pustular psoriasis, Nail psoriasis, Guttate psoriasis, Flexural psoriasis, Erythrodermic psoriasis. Activated T cells go into the skin from the circulation and lymph nodes and release cytokines (INF, IL-2) that cause pathologic alterations. Other cytokines like TNF- and IL-8 are produced locally by neutrophils and keratinocytes. Keratinocyte proliferation is a result of T-cell generation and activation. Histocompatibility studies show relationships between histocompatibility antigens and HLA-C6, TNF, and IL-3.1) · T-helper ½, · Th17 & Th17 Cytokines, · Dendritic cells, IL-23 and TNF-α. They have many causes that help in develop the psoriasis are · Genetics, · Lifestyle, · HIV, · Microbes, · Medications. They have many treatment therapies are- Topical therapy- · Corticosteroids, · Calcipotriene, Tazarotene.
Psoriasis is a chronic inflammatory skin disease induced by multifactorial causes and is characterized by bothersome, scaly reddish plaques, especially on frequently chafed body parts, such as extensor sites of the extremities. The latest advances in molecular-targeted therapies using biologics or small-molecule inhibitors help to sufficiently treat even the most severe psoriatic symptoms and the extra cutaneous comorbidities of psoriatic arthritis. The excellent clinical effects of these therapies provide a deeper understanding of the impaired quality of life caused by this disease and the detailed molecular mechanism in which the interleukin (IL)-23/IL-17 axis plays an essential role. To establish standardized therapeutic strategies, biomarkers that define deep remission are indispensable. Several molecules, such as cytokines, chemokines, antimicrobial peptides, and proteinase inhibitors, have been recognized as potent biomarker candidates. In particular, blood protein markers that are repeatedly measurable can be extremely useful in daily clinical practice. Herein, we summarize the molecular mechanism of psoriasis, and we describe the functions and induction mechanisms of these biomarker candidates.
Psoriasis is a multifactorial recalcitrant inflammatory skin disease characterized by bothersome scaly reddish plaques especially on frequently chafed body parts, such as the extensor sites of the extremities and scalp. Nonetheless, through recent advance in molecular‐targeted therapies including biologics and small‐molecule inhibitors, even the severest symptoms of psoriasis and its comorbidities, such as psoriatic arthritis, can be excellently treated. The superb clinical effects lead to not only remarkable alleviation of symptoms but also a deep understanding of patients’ impaired “quality of life” caused by this disease. Along with the development of novel treatment options targeting various specific molecules, such as proinflammatory cytokines and signal transduction‐associated molecules, clinicians have thoroughly understood the molecular mechanism of psoriasis, and discovered that the IL‐23/IL‐17 axis mainly depending on Th17 cell function is a crucial pathogenesis of this disease. Accumulation of knowledge about the working mechanism and clinical effect of molecular‐targeted therapies is indispensable for clinicians to establish a more refined therapeutic strategy for treating psoriasis.
This review paper discusses the systemic character of psoriasis. For medical specialists, it is of crucial importance to understand that psoriasis is not exclusively a skin disease; rather, it is pathogenetically connected with the development of a number of comorbid conditions. This fact has a practical significance in terms of choosing therapeutic strategies for managing patients with medium and severe dermatoses characterized by relapses and comorbid conditions. The long-term use of systemic medications in such cases, including genetically engineered biological ones, seems to be theoretically reasonable, since it facilitates control over the main clinical manifestations of the disease.This paper presents information on the innovative Russian drug — BCD-085-inhibitor IL17 — and its effects on the key stages of psoriasis immunopathogenesis. The efficacy and safety of this drug for patients with moderate and severe psoriasis are discussed.BCD-085 is found to exhibit a fast and high therapeutic response in terms of the PASI75, PASI90, PASI100 and sPGA indexes during the first 12 weeks of therapy. According to the available data, BCD-085 is characterized by a favourable safety profile and the absence of immunogenicity from the clinical standpoint.
Introduction: Biologic therapy has revolutionized treatment pathways in psoriatic joint and skin disease. It has also provided a useful tool with which pathological pathways of this condition may be explored.
Areas Covered: This review presents data on the clinical and biological effects of targeted therapy in psoriatic arthritis and psoriasis. Therapeutic agents covered include inhibitors of TNFα, inhibitors of the IL-23/IL-17 axis and inhibitors of intracellular small molecules involved in the transduction of the inflammatory signal. Trial data on clinical and imaging efficacy is reviewed in parallel with studies on biological effects at tissue level. Pathological insights gained from the use of these treatments are explored.
Expert Commentary: A close relationship exists between specific pathological types and clinical manifestations of psoriatic disease, including responses to treatment. Studying these relationships is likely to improve understanding of disease and enable rational selection of specific treatments for patients with specific pathotypes.
Introduction:
Biological agents have transformed psoriasis treatment by selectively targeting immune signaling molecules involved in psoriasis pathogenesis. While biologics offer the most effective treatment of moderate to severe psoriasis, they are not without complications. Some patients treated with biologics have poor clinical responses, form anti-drug antibodies, or develop adverse events. Additionally, there is growing need for head-to-head studies comparing biologic treatment regimens, efficacy, and safety.
Areas covered:
Here we review the literature surrounding biologics already in clinical use and those undergoing development and clinical trials. We also investigate the development and approval of small molecules inhibitors and biosimilars used to treat psoriasis. Expert Commentary: As the psoriasis treatment armamentarium continues to expand, it is important to follow the safety profile of these drugs both in clinical trials and in post-marketing registries to ensure their long-term safety. Physicians must be aware of the limitations of existing safety data of a drug and the potential risk for rare adverse events when selecting appropriate treatments and monitoring patient outcomes.
In recent years, there have been many exciting advances made in the field of inflammation.
State of the art scientific technologies have helped make these advances possible. As
underlying cellular and biochemical mechanisms responsible for the inflammatory response
are better understood, new therapeutic strategies can be developed to treat the spectrum of
clinical problems associated with excessive inflammation.
This educational eBook, “Basic Biology and Clinical Aspects of Inflammation” was
developed for a wide audience. Basic scientists, academicians, clinicians, health care
regulators, industrial and pharmaceutical scientists as well as the lay public can benefit from
the expanse of knowledge presented herein.
To help continue promoting cutting edge scientific research and technology, the Editors and
all contributing Authors have agreed to donate their royalties from this eBook to the Wound
Healing Foundation (http://www.woundhealingfoundation.org) for young investigator
research grants. In addition, we recognize and appreciate Bentham Science Publishers for
their generous support and contributions to the Wound Healing Foundation.
Background:
Tumor necrosis factor-α inhibitors (TNFi) are the most widely used systemic treatments for patients with psoriasis and psoriatic arthritis. There currently exists a U.S. Food and Drug Administration issued warning label on all TNFi for "rare cases of new onset or exacerbation of central nervous system demyelinating disorders." The aim of this review was to update the incidence of TNFi-induced demyelinating diseases.
Methods:
Pubmed database was searched for safety data regarding demyelinating disease secondary to TNFi therapy prescribed for psoriasis.
Results:
In clinical trials: 6990 patients had received treatment with etanercept with one reported case of multiple sclerosis; 5204 patients were treated with adalimumab with no cases identified and 2322 patients were treated with infliximab with one case of demyelinating polyneuropathy. Outside of clinical trials: 19 individual cases of demyelinating disorders from TNFi treatment have been reported.
Conclusion:
Although there is potential for TNF blockade to lead to demyelination of the central and peripheral nervous systems, the results of the present review suggest that demyelinating diseases associated with TNFi are extremely rare. TNFi are not recommended for use in patients with a personal history of demyelinating disease. However, with clinical vigilance and individualized treatment regimen, TNFi may be safe for use in other patients.
Autoimmune diseases are a type of diseases arising from an abnormal immune response of the body against substances and tissues normally present in the body, which cause tissue or organ damages. Conventional chemical drugs are usually aimed at alleviating pain or the symptoms without achieving a significant therapeutic effect. The development of life science and the study of signal pathway and relevant target proteins of the body get further monoclonal antibodies and Fc fusion proteins. Meanwhile the research and technological improvement of antibody drugs goes deeper in recent years, which have accelerated the development in this field. On the basis, relevant drugs are currently becoming a hot treatment of autoimmune diseases. To date, there have been more than 10 relevant products in the market, mainly specifically targeting TNF, some of the IL families and a few other target proteins.
Purpose: The aim of this Case Report is to explain the effect of undiagnosed ocular cicatricial pemphigoid (OCP), the importance of early diagnosis, and the role optometrists play in the management of OCP. Method: This article will use a 53-year-old white male with a history of chronic conjunctivitis to help illustrate OCP. Result: The exam findings revealed inferior temporal Symblepharon and granulomas on the palpebral conjunctiva of both eyes. Once biopsies of the eyelid growths led to a definitive diagnosis of OCP, the patient was treated orally with 60 mg of prednisone daily. Future treatment options include the use of immunosuppressive drugs. Conclusion: OCP is frequently diagnosed in advanced stages. Therefore, aggressive treatment is often necessary. As optometrists, our goal is to recognize this condition as early as possible and to initiate treatment before vision loss occurs.
Background:
Psoriasis is a chronic skin disease that may develop at any age. Estimates for the United States and Europe suggest that psoriasis accounts for 4% of skin diseases in children. In most cases, the condition is mild and can be treated with creams. However, a small percentage of children have moderate to severe disease that requires drugs, such as ciclosporin or methotrexate, and some will require injections with newer biological agents, such as anti-TNF (tumour necrosis factor) drugs. Anti-TNF drugs (among them etanercept, infliximab, and adalimumab) are designed to reduce inflammation in the body caused by tumour necrosis factor. Evidence for the safety and efficacy of these biological agents in paediatric psoriasis is lacking.
Objectives:
To assess the efficacy and safety of anti-TNF agents for the treatment of paediatric psoriasis.
Search methods:
We searched the following databases up to July 2015: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), and LILACS (from 1982). We also searched 13 trials registers and checked the reference lists of included studies and key review articles for further references to relevant randomised controlled trials (RCTs). We handsearched conference proceedings and attempted to contact trial authors and relevant pharmaceutical manufacturers. We searched the US Food and Drug Administration's and European Medicines Agency's adverse effects databases.
Selection criteria:
All relevant RCTs that evaluated the efficacy and safety of anti-TNF agents for the treatment of chronic plaque psoriasis in individuals less than 18 years of age.
Data collection and analysis:
Two review authors independently checked titles and abstracts and performed data extraction and 'Risk of bias' assessment of the included studies. One review author entered data into Review Manager (RevMan), and a second review author checked the data. We also attempted to obtain unclear data from the trial authors where possible.Our primary outcomes were investigator-assessed number of participants achieving a 75% improvement in Psoriasis Area and Severity Index-75 (PASI 75) compared to baseline, improvement in quality of life using an instrument such as Children's Dermatology Life Quality Index (CDLQI), and adverse effects. Our secondary outcomes included the proportion of participants achieving PASI 50 and the Physician's Global Assessment (PGA).
Main results:
We included one study with 211 participants (median age 13 years), in which etanercept (dosage ranged from 0.8 to 50 mg per kilogram of body weight) was compared to placebo. Follow-up was over a 48-week period.At week 12, 57% versus 11% who received etanercept or placebo, respectively, achieved the PASI 75 (risk ratio 4.95, 95% confidence interval (CI) 2.83 to 8.65; high-quality evidence). Absolute risk reduction and the number needed to treat to obtain a benefit with etanercept was 45% (95% CI 33.95 to 56.40) and 2 (95% CI 1.77 to 2.95), respectively.The percentage improvement from baseline of the CDLQI scores at week 12 was better in the etanercept group than the placebo group (52.3% versus 17.5%, respectively (P = 0.0001)). Analysis between the groups showed an effect size that was clinically important (mean difference 2.30, 95% CI 0.85 to 3.75; high-quality evidence). However, means, medians, and minimal important difference results and results of the Pediatric Quality of Life Inventory, Stein Impact on Family Scale, and Harter Self-Perception Profile for Children scores must be interpreted with caution, as they were not prespecified outcomes.Three serious adverse events were reported, but they were resolved without sequelae. Deaths or other events such as malignant tumours, opportunistic infections, tuberculosis, or demyelination were not reported in the included study.Also, 13% of participants in the placebo group and 53% in the etanercept group had a PGA of clear or almost clear (risk ratio 3.96, 95% CI 2.36 to 6.66; high-quality evidence) at week 12.
Authors' conclusions:
This review found only one RCT evaluating the use of this type of biological therapy. Although the risk of publication bias was high, as we included only one industry-sponsored RCT, the risk of allocation, selection, performance, attrition, and selective reporting biases for all outcomes (except for CDLQI) was low, and no short-term serious adverse events were found.We can conclude, based on this single included study, that etanercept seems to be efficacious and safe (at least in the short term) for the treatment of paediatric psoriasis. However, as the GRADE approach refers not to individual studies but to a body of evidence, we shall wait for the results of the ongoing studies in a future update of this review. In addition, future studies should evaluate quality-of-life endpoints established a priori and standardise primary outcome measures such as PASI 75, and should include the PGA as a secondary endpoint. Also, collating and reporting adverse events uniformly is required to better evaluate safety.
CONCLUSION Le psoriasis reste une maladie chronique malgré le développement récent de tout un arsenal de nouvelles stratégies thérapeutiques adaptées à tous les degrés de sévérité de la maladie. Le traitement optimal diffère d'un sujet à l'autre et l'établissement d'une prise en charge adéquate implique la considération de multiples facteurs individuels. Le traitement combiné et alterné (topique et systémique), indiqué dans toutes les formes, permet de bénéficier d'une efficacité maximale tout en réduisant l'incidence des effets secondaires immédiats et tardifs de chaque traitement individuel. L'introduction des nouveaux traitements biologiques soulève l'espoir de pouvoir bientôt bénéficier, par analogie aux DMARDs (disease modifying anti rheumatic drugs), de DMAPDs (disease modifying antipsoriatic drugs), permettant de contrôler la maladie et de la rendre acceptable aux yeux des patients concernés sans pour autant l'éradiquer définitivement.
The successful introduction of anti-tumor necrosis factor (TNF) therapies in psoriasis and psoriatic arthritis has sharpened
considerable interest in this chronic and frequently disabling disease. Unlike the situation in rheumatoid arthritis, where
anti-TNF therapies were introduced after years of painstaking research which confirmed a key proinflammatory role for TNF,
the evidence for TNF having a key role in psoriatic arthritis has lagged behind. In this paper, the emerging immunohistochemical,
genetic, and clinical literature relating to TNF’s role in skin and joint manifestations of this disease is reviewed and areas
for future research are suggested.
The interleukin (IL)-12 family of cytokines, including IL-12 and IL-23, are important mediators of immune-mediated inflammatory diseases such as psoriasis, multiple sclerosis, rheumatoid arthritis, and Crohn's disease. Interleukin-12 and IL-23 are heterodimeric proteins composed of the common subunit IL-12 p40, which interacts with the IL-12Rβ1 receptor, and the cytokine-specific subunits IL-12 p35 and IL-23 p19, respectively. The cytokines are proinflammatory factors linking innate and adaptive immune responses via the induction and differentiation of the T helper cell 1 pathway. Interleukin-12 and IL-23 target different subpopulations of T cells and antigen-presenting cells, as evidenced by their slightly different, but possibly clinically significant, characteristics and functions. Because both share the p40 subunit, the use of anti-IL-12 antibodies may not be as clinically effective as the use of anti-IL-12 p40 antibodies, since both IL-12 and IL-23 share the subunit, which compete, for the IL-12Rβ1 receptor. Also, while IL-12 is a key factor that drives T helper cell 1 responses and interferon-gamma production in the early phases of the immune responses, it may play a relatively minor immunoregulatory role in late-stage inflammation at the point when IL-23 strongly supports the inflammatory process. Thus, direct IL-23 blockade may be key in treating some inflammatory autoimmune diseases as we further define the roles and functions of IL-12 and IL-23. Research into the function and regulation of IL-12 and IL-23 is a promising area of study for inflammatory disease mediation, and inhibition of their actions may have clinical therapeutic applications.
The effect of CP-690550 (tofacitinib), a new Janus kinase (JAK) inhibitor, was evaluated in chronic allergic dermatitis. Allergic contact dermatitis was induced in rat ears by repeated application of oxazolone. This dermatitis was accompanied by sustained ear swelling and marked epidermal hyperplasia. In the induced ear, a lot of inflammatory cells infiltrated into the dermis site and the amounts of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-22 were elevated. Orally administered CP-690550 significantly suppressed ear swelling as well as epidermal thickening, and the effect at 10 mg/kg was comparable to that of cyclosporin A and etanercept. These results suggest a great potential of CP-690550, a JAK inhibitor, as a treatment for chronic dermatitis featuring epidermal hyperplasia (in the pathogenesis of which IFN-γ, TNF-α and IL-22 play a role) such as psoriasis and chronic atopic dermatitis.
Anti-tumor necrosis factor (TNF) biologic drugs are among the most important advances recently introduced in the treatment of psoriasis. These drugs have modified the traditional view of psoriasis pathogenesis and have changed the approach to the disease and its management. Etanercept and infliximab are the only TNF inhibitors currently approved for plaque psoriasis. Adalimumab is in Phase III trials for this indication. All these drugs are approved for the treatment of psoriatic arthritis. Other TNF-targeting agents are under investigation for psoriasis and other diseases. This article briefly reviews the current knowledge of TNF blockers in psoriasis, with emphasis on pharmacologic profile, mechanism of action, immunogenicity, efficacy, safety, novel aspects related to clinical use (dose, regimens and long-term management) and European and US prescribing guidelines.
Psoriasis is a multifactorial disease, its pathogenesis combining hereditary and environmental factors. This affliction is characterized by a large polymorphism of cutaneous lesions, but also by its association with inflammatory articular manifestations which are by far the most frequent extra-cutaneous complication. Although the link between cutaneous lesions and articular manifestations remains for a large part a mystery, recent advances in immunopathology now permit a better understanding of certain similarities and differences.
To analyse more precisely the differences and similarities between psoriasis and psoriatic arthritis, it is of interest to study successively:
Psoriatic arthritis is not a synovial form of psoriasis, as evidenced by genetic and immune differences. The specific determinants that favour the appearance of articular symptoms are yet to be more precisely identified, even in patients displaying minimal cutaneous lesions.
The aim of this study was to investigate the cumulated incidence and clinical characteristics of the psoriasiform lesions seen in a wide cohort of rheumatic patients exposed to anti-TNFα drugs in a tertiary care hospital from northern Spain. The study population included 450 patients exposed to anti-TNFα agents from 2001 to 2007 and treated in a university hospital in northern Spain. Two hundred patients were exposed to infliximab (44%), 129 (29%) to etanercept, and 121 (27%) to adalimumab. The cumulated incidence (CI) of this skin reaction was calculated for each of the three agents studied. Psoriasis and psoriasiform lesions were documented in 7 patients diagnosed with different rheumatic inflammatory conditions (1.56%). Cases of this adverse effect were identified with all three anti-TNFα agents available at that time, but less frequently with infliximab (CI: 0.5%) compared with etanercept (CI: 2.3%) or adalimumab (CI: 2.5%). The most common lesion was palmoplantar pustulosis (71.3% of the cases), and the latency period to the development of the lesions ranged from 4 to 38 months (mean 9 months). In four of the 7 patients, treatment was suspended, while in the remaining three patients treatment was continued. The CI of this skin reaction in our setting is similar to that published by others. Infliximab was found to be less frequently associated with this adverse event. In our experience, it is not always necessary to stop anti-TNFα therapy for the skin lesions to improve.
Background Monoclonal gammopathies are haematological conditions characterized by the clonal proliferation of plasma cells which produce a monoclonal immunoglobulin that accumulates in the blood. They have already been reported during treatment with a range of drugs but never before during treatment with the anti-TNF-α treatments: adalimumab, etanercept and infliximab currently used in the therapy of moderate-severe psoriasis and psoriatic arthritis.
Objective This is a case series describing the development of MGUS in psoriatic patients treated with anti-TNF-α.
Methods Three hundred patients receiving an anti-TNF-α treatment for chronic plaque psoriasis or psoriatic arthritis in a clinical setting in Italy, These patients were screened through serum protein electrophoresis to investigate the possible development of MGUS.
Results Eight patients were found to have developed monoclonal gammopathy of undetermined significance. The median treatment duration for the eight patients was 1 year with excessive IgG present in five patients, IgM accumulation in one patient and a double monoclonal component in two patients.
Conclusion Our data suggest that there may be an association between anti-TNF-α therapy and development of MGUS.
Psoriasis is well known as a chronic inflammatory dermatosis. The disease affects persons of all ages and is a burden worldwide. Psoriasis is associated with various diseases such as arthritis. The disease is characterized by well-demarcated lesions on the skin of the elbows and knees. Various genetic and environmental factors are related to the pathogenesis of psoriasis. In order to identify enzymes that are potential therapeutic targets for psoriasis, we utilized a computational approach, combining microarray analysis and protein interaction prediction. We found 6,437 genes (3,264 upregulated and 3,173 downregulated) that have significant differences in expression between regions with and without lesions in psoriasis patients. We identified potential candidates through protein-protein interaction predictions made using various protein interaction resources. By analyzing the hub protein of the networks with metrics such as degree and centrality, we detected 32 potential therapeutic candidates. After filtering these candidates through the ENZYME nomenclature database, we selected 5 enzymes: DNA helicase (RUVBL2), proteasome endopeptidase complex (PSMA2), nonspecific protein-tyrosine kinase (ZAP70), I-kappa-B kinase (IKBKE), and receptor protein-tyrosine kinase (EGFR). We adopted a computational approach to detect potential therapeutic targets; this approach may become an effective strategy for the discovery of new drug targets for psoriasis.
Psoriasis is a common dermatosis affecting the skin, mucosal surfaces, and cutaneous adnexa, and joints and bones can be involved at some degree in the clinical features of the disease, configuring psoriatic arthritis. Moderate to severe psoriasis has a high impact on quality of life and requires an integrated and long-term treatment schedule. However, management of psoriasis in patients affected by other systemic diseases can be challenging because of the possible side effects or contraindications of various treatments in accordance with patients' medical history. In recent times, the therapeutical approaches have changed a lot, thanks to biologicals. The current authors present some cases of psoriatic patients with comorbidities successfully treated with efalizumab, an anti-T lymphocyte biological.
Fibroblast growth factor receptor 4 (FGFR4) is a transmembrane tyrosine kinase receptor that plays a crucial role in the regulation of hepatic bile acid and lipid metabolism. FGFR4 underlies high-fat diet-induced hepatic steatosis, suggesting that inhibition of FGFR4 activation may be an effective way to prevent or treat nonalcoholic fatty liver disease (NAFLD). To determine whether neutralization of FGFR4 ligands by soluble FGFR4 extracellular domain (FGFR4-ECD) can inhibit the activation of FGFR4, we constructed FGFR4-ECD expression vector and showed that FGFR4-ECD was effectively expressed in cells and secreted into culture medium. FGFR4-ECD inhibited FGF19-induced activation of FGFR4 signaling and reduced steatosis of HepG2 induced by palmitic acid in vitro. Furthermore, in a tetracycline-induced fatty liver model, expression of FGFR4-ECD in mouse liver reduced the accumulation of hepatic lipids and partially restored the expression of peroxisome proliferator-activated receptor α (PPARα), which promotes the mitochondrial fatty acid beta-oxidation but is repressed by tetracycline. Taken together, these results demonstrate that FGFR4-ECD can block FGFR4 signaling and prevent hepatic steatosis, highlighting the potential value of inhibition of FGFR4 signaling as a method for therapeutic intervention against NAFLD.
Introduction:
Conventional systemic therapies for psoriasis are associated with serious toxicities that can limit long-term use. In recent years, biological therapies have offered the possibility of long-term therapy with improved safety and efficacy for the treatment of psoriasis. Biological therapies can be classified into three categories: the T-cell modulating agents (alefacept and efalizumab), the inhibitors of TNF-α (adalimumab, etanercept, infliximab) and the inhibitors of IL-12 and -23 (ustekinumab). Efalizumab is a humanized recombinant monoclonal IgG1 antibody. It targets multiple stages in the immunopathogenesis of psoriasis: initial T-cell activation, migration of T-cells into dermal and epidermal tissues, and T-cell reactivation. On 19 February 2009, the Committee for Medicinal Products for Human Use (CHMP) recommended the suspension of the marketing authorisation for efalizumab.
Areas covered:
Numerous clinical trials have demonstrated the efficacy, safety and health-related quality of life benefits of efalizumab in patients with moderate-to-severe chronic plaque psoriasis. Efalizumab was approved by the FDA in November 2003 and by the European Medicines Evaluation Agency in September 2004 for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. Recently, three cases of progressive multifocal leukoencephalopathy were described in patients on long-term (> 3 years) efalizumab therapy, leading to its withdrawal from the market.
Expert opinion:
Although initially favorable, the safety profile of efalizumab revealed the appearance of severe adverse events in long-term treated patients. Therefore, post-marketing surveillance is essential for correct evaluation of drug potential.
Recent epidemiological observations reveal that the prevalence of psoriasis increases more rapidly in young women compared with young men, and that the prevalence of psoriasis may decrease in the elderly. Emerging evidence suggests that some potentially modifiable exposures, such as smoking, stress and obesity, may increase a patient's risk of developing psoriasis. The evolving literature suggests that psoriasis is associated with multiple other diseases, including cancer, cardiovascular disease, diabetes and psychiatric disease, and that psoriasis itself may be an independent risk factor for developing atherosclerosis and myocardial infarction. The treatment of moderate-to-severe psoriasis is undergoing a revolution with the advent of biological therapies that target the immunopathogenesis of psoriasis, such as tumor necrosis factor-alpha and T-cell function. The pharmacokinetics, pharmacodynamics, efficacy and safety profiles vary among biologicals and, therefore, drug and patient factors are important in selecting the optimum therapy. In this article, we focus on recent developments in the epidemiology and systemic treatment of psoriasis.
The migration of memory T-cells to sites of inflammation is a multistep process controlled by an array of specific receptor-ligand pairs. Chemokines and their receptors represent a central paradigm of the molecular basis of the skin-homing of T-cells. Although CCR4 and CCR10 are both associated with conventionally defined skin-homing T-cells, the association is not necessarily perfect. Interaction between E-selectin and its ligand may represent more specific targets for therapeutic intervention. Although fucosyl transferase?VII is essential for generating E-selectin ligands necessary for T-cell homing to skin, fucosyltransferase-IV, another fucosyltransferase expressed to a significant degree in T-cells, can also generate E-selectin ligands. The induction and upregulation of both enzymes can be co-ordinately regulated depending on their state of activation and differentiation and the cytokine milieu. The dynamic balance between the two enzymes is a major check point for the regulation of skin-homing T-cell differentiation. Polarized T-cells regulate their adhesions on a minute-to-minute basis depending on the cytokine environment. Soluble adhesion molecules found to be increased in chronic inflammatory skin diseases may serve to limit the duration or magnitude of T-cell recruitment. In addition to T-cells migrating from the circulation, T-cells indigenously residing in the tissue itself, such as skin-resident T-cells, would also be responsible for tissue damage. It should also be appreciated that T-cell recruitment to the skin is critical for host defense and that no definitive means exist to distinguish protective regulatory T-cells from pathogenic T-cells.
Fifteen serum samples and 29 synovial fluids of patients with rheumatoid arthritis (RA) were examined for the presence of tumour necrosis factor (TNF). The assay for TNF was based on the cytotoxic activity of this cytokine for human melanoma cells in tissue culture. High concentrations of TNF were found in serum samples of patients with severe RA, who had increased erythrocyte sedimentation rate and serum alpha 2 macroglobulin, but decreased haemoglobin and serum iron concentrations. Tumour necrosis factor was also found in the synovial fluid of 16 out of 29 patients. High TNF concentrations were found in fluids with greater than 10(10) leucocytes/l. Tumour necrosis factor was not detected in the serum of normal subjects or in synovial fluid of patients with osteoarthritis. A mediator of inflammation, such as TNF, may contribute to the severity of RA.
Expression of the pluripotent molecule TNF in a focused and antigen-restricted fashion might provide an advantage to the host organism. Given the central role of T cells in antigen-specific immunity, we examined whether activated T cells express TNF on their cell surface. FACS analysis of highly purified normal human T cells labeled with an anti-TNF mAb revealed that T cells express cell surface TNF when signaled with the synergistic combination of a calcium ionophore, ionomycin, and a protein kinase C activator, 12-o-tetradecanoyl phorbol acetate. Cell surface radioiodination studies of stimulated T cells demonstrated the presence of 26-kD transmembrane protein, a size predicted by TNF cDNA and different from that of the 17-kD secreted TNF molecule. The induced cell surface expression of TNF could be blocked with cyclosporine and/or methylprednisolone, and Northern analysis for TNF-specific transcripts revealed that this inhibitory effect occurs pretranslationally. Our demonstration for the first time that stimulated normal human T cells display cell surface TNF provides a mechanistic basis for the realization of effects of TNF in an antigen-specific fashion.
T lymphocytes infiltrate wounds, tumors, and atherosclerotic plaques, pathophysiological processes characterized by the migration and proliferation of vascular cells and fibroblasts. Although T lymphocytes are known to produce cytokines for inflammatory cells, it has not been demonstrated that they synthesize growth factors that are mitogenic for vascular cells and fibroblasts. We demonstrate that cultured T lymphocytes isolated from normal human peripheral blood synthesize and export two well-characterized growth factors, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and basic fibroblast growth factor (bFGF). This conclusion is based on mRNA expression analysis, heparin-affinity chromatography profiles, target-cell specificity, and functional inhibition by specific neutralizing antibodies. Atypically, a substantial amount of T-cell-derived bFGF-like activity appears to be constitutively released into conditioned medium, almost as much as is associated with T-cell lysates. bFGF is synthesized and exported by purified CD4+ and CD8+ T cells, whereas HB-EGF is synthesized and exported primarily by CD4+ T cells. The T-cell-derived HB-EGF and bFGF activities are potent mitogens for fibroblasts and smooth muscle cells, and the bFGF-like activity is also mitogenic for endothelial cells. These results suggest that T lymphocytes may play key roles in mediating smooth muscle hyperplasia associated with atherosclerosis and in angiogenesis associated with wound healing and tumor growth by acting locally to deliver vascular-cell growth factors to tissues.
Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc).
In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria.
Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples.
In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.
Accumulation of polymorphonuclear neutrophils (PMN) into the subarachnoidal space is one of the hallmarks of Neisseria meningitidis infection. In this study, we evaluated the ability of outer membrane vesicles (OMV) from N. meningitidis B to stimulate cytokine production by neutrophils. We found that PMN stimulated in vitro by OMV produce proinflammatory cytokines
and chemokines including tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-8, macrophage inflammatory protein
1α (MIP-1α), and MIP-1β. A considerable induction of gamma interferon (IFN-γ)-inducible protein 10 (IP-10) mRNA transcripts,
as well as extracellular IP-10 release, was also observed when neutrophils were stimulated by OMV in combination with IFN-γ.
Furthermore, PMN stimulated by OMV in the presence of IFN-γ demonstrated an enhanced capacity to release TNF-α, IL-1β, IL-8,
and MIP-1β compared to stimulation with OMV alone. In line with its downregulatory effects on neutrophil-derived proinflammatory
cytokines, IL-10 potently inhibited TNF-α, IL-1β, IL-8, and MIP-1β production triggered by OMV. Finally, a neutralizing anti-TNF-α
monoclonal antibody (MAb) did not influence the release of IL-8 and MIP-1β induced by OMV, therefore excluding a role for
endogenous TNF-α in mediating the induction of chemokine release by OMV. In contrast, the ability of lipopolysaccharide fromN. meningitidis B to induce the production of IL-8 and MIP-1β was significantly inhibited by anti-TNF-α MAb. Our results establish that,
in response to OMV, neutrophils produce a proinflammatory profile of cytokines and chemokines which may not only play a role
in the pathogenesis of meningitis but may also contribute to the development of protective immunity to serogroup B meningococci.
Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate.
In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks.
At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.
During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.
Immunocompetent cells in exacerbating untreated psoriasis vulgaris skin lesions were immunophenotypically studied by the application of a selection of monoclonal antibodies in a two-stage immunoperoxidase technique. Epidermal changes include: focal accumulation of immunoglobulins in the stratum corneum, as demonstrated by a mixture of monoclonal anti-kappa and anti-lambda antibodies; focal accumulation of OKM-1 positive but Mo-2 negative cells high in the epidermis, reflecting granulocytes in Munro's abcesses; a marked decrease in epidermal Langerhans cells with focal abnormal clumping and smaller dendrites, as demonstrated by monoclonal anti-HLA-DR and anti-T6 (OKT-6) antibodies; and, sporadic exocytosis of mainly T1 (Leu-1), T8 (Leu-2a) positive suppressor/cytotoxic T lymphocytes.
The dermal infiltrates were found to consist mainly of partically activated T1 (Leu-1), T4 (Leu-3a) positive T-helper/inducer cells with a smaller compartment of T1 (Leu-1), T8 (Leu-2a) positive suppressor/cytotoxic lymphocytes. These cells were found in close apposition to T6 (OKT-6), HLA-DR positive Langerhans cells and further accompanied by a minor compartment of OKM-1, Mo-2 positive monocytes. No B-cells or plasma cells could be demonstrated in the dermis. Natural killer cells were observed only incidentally.
These results fit best with the hypothesis that psoriasis is a chronic inflammatory condition as a result of persistant stimulation of T cells by immunogen(s) of epidermal origin.
Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report, we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-alpha within granules, which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells, mast cells are the predominant cell type that expresses both TNF-alpha protein and TNF-alpha mRNA. Moreover, induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-alpha. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion.
Staphylococcal enterotoxin at concentrations of less than 1 pg/ml induces significant TNF activity in human peripheral blood T cells and monocytes. Maximal TNF activity is routinely detected after 48 to 72 h of culture. IL-2 and IL-4 were both growth promoting for human T cells but only IL-2 could efficiently induce TNF production. The production of TNF-alpha and TNF-beta differed greatly in kinetics. An early intracytoplasmatic production of TNF-alpha after 6 h was detected in both monocytes and T cells whereas a late production of TNF-beta (lymphotoxin) after 48 h, occurred in the T cell population. Induction of TNF-alpha and TNF-beta production by Staphylococcal enterotoxin requires the presence of both monocytes and T cells. The CD4+45R- but not CD4+45R+ and CD8+ cells supported TNF-alpha production in monocytes. The main lytic component from Staphylococcal enterotoxin-activated mononuclear cells is TNF-beta. CD4+ and CD8+ T cells produced about equal amounts of biologically active TNF into the culture supernatants but a fourfold higher frequency of TNF-beta producing cells was demonstrated among CD4+ vs CD8+ cells. The CD4+45R- T cell subset was an efficient producer of TNF-beta and IFN-gamma whereas the CD4+45R+ T cell subset produced significant amounts of TNF-beta but only marginal amounts of IFN-gamma.
Tumor necrosis factor and immune interferon synergistically increase cell-surface expression of class I major histocompatibility complex molecules in cultured human endothelial cells. We report that tumor necrosis factor and interferon gamma each independently increase mRNA levels and together cause a greater-than-additive (i.e., synergistic) increase in steady-state mRNA levels and transcriptional rates of the class I heavy- and light-chain genes. HLA heavy-chain mRNA is equally stable in cytokine-treated and -untreated endothelial cells. Interferon gamma does not increase tumor necrosis factor receptor number or affinity on human endothelial cells. We conclude that the synergistic increase in class I major histocompatibility complex cell-surface expression results principally from the synergistic increase in transcriptional rates. We propose that this increase is caused by the cooperative binding of independently activated transcription factors to the promoter/enhancer sequences of class I genes.
Keratinocytes and fibroblasts isolated from human neonatal foreskin can be plated and grown through multiple rounds of division in vitro under defined serum-free conditions. We utilized these growth conditions to examine the mitogenic potential of acidic and basic fibroblast growth factor (aFGF and bFGF) on these cells. Our results demonstrate that both aFGF and bFGF can stimulate the proliferation of keratinocytes and fibroblasts. aFGF is a more potent mitogen than bFGF for keratinocytes. In contrast, bFGF appears to be more potent than aFGF in stimulating the growth of fibroblast cultures. Heparin sulfate (10 micrograms/ml) dramatically inhibited the ability of bFGF to stimulate the proliferation of keratinocytes. In comparison, heparin slightly inhibited the stimulatory effect of aFGF and had no effect on epidermal growth factor (EGF) stimulation in keratinocyte cultures. In fibroblast cultures the addition of heparin enhanced the mitogenic effect of aFGF, had a minimal stimulatory effect on the mitogenic activity of bFGF, and had no effect on EGF-stimulated growth. Our results demonstrate that the proliferation in vitro of two normal cell types found in the skin can be influenced by aFGF and bFGF and demonstrate cell-type specific differences in the responsiveness of fibroblasts and keratinocytes to these growth factors and heparin.
Lymphocytes bind to cultured keratinocytes that are treated with interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). When the lymphocytes are preincubated with antibody to lymphocyte function associated antigen-1 (LFA-1), this adherence is inhibited. Because intercellular adhesion molecule-1 (ICAM-1) is a ligand for LFA-1, we studied the cellular expression of ICAM-1, as well as two other IFN-gamma-inducible antigens, (HLA) human lymphocyte antigens DR and DQ, in both normal and diseased skin. The modulation of these cell surface antigens by IFN-gamma and TNF with the use of short-term organ cultures of skin was compared with isolated keratinocytes grown in a conventional tissue culture system. While in normal skin, keratinocytes did not express HLA-DR, DQ, or ICAM-1, when organ cultures were supplemented with IFN-gamma, rapid induction of keratinocyte ICAM-1 expression occurred after 24 hours; HLA-DR but not DQ expression occurred after 48 hours. TNF also induced keratinocyte ICAM-1 expression (although to a lesser degree than IFN-gamma) but did not induce either keratinocyte HLA-DR or DQ expression. There was good correlation of keratinocyte expression of ICAM-1 and HLA-DR by IFN-gamma and TNF when the epidermis of the organ culture system was compared with the isolated keratinocytes grown in tissue culture. The presence of intraepidermal lymphocytes correlated extremely well with keratinocyte ICAM-1 expression but not with keratinocyte HLA-DR expression in psoriasis, atopic dermatitis, lichen planus, and mycosis fungoides. The intensity of endothelial cell expression of ICAM-1 correlated with the degree of dermal inflammation. We conclude that IFN-gamma, once produced by activated T lymphocytes in the dermis, may be of importance in lymphocyte trafficking in the epidermis by the induction of keratinocyte ICAM-1 expression. The use of the short-term organ culture system, in which there is inducible ICAM-1 expression, provides an experimental bridge between purely in vitro and in vivo investigations to further our understanding of the molecular basis for lymphocyte apposition to keratinocytes in the skin.
Macrophage-derived tumor necrosis factor (TNF) is increasingly being recognized as an important monokine possessing multifunctional activities. Current evidence has demonstrated that TNF can induce a number of pleomorphic effects in both physiological and immunological systems. Historically, the biological effects and nomenclature of TNF centered around the induction of hemorrhagic necrosis of specific solid murine tumors. This effected function has been greatly expanded upon, and TNF is now recognized as an important peptide mediator involved in various facets of cell activation. This is exemplified by the central role that TNF plays in endotoxemia, shock and multiple organ failure syndromes. Although TNF has been incriminated as the molecular signal mediating number of pathophysiological derangements, the regulatory mechanisms that control TNF expression at the cellular and molecular levels, as well as the modulation of the in vivo activity of preformed TNF, has not been full addressed. In this review, a detailed description of the mechanisms that regulate the production and effects of TNF is presented.
We have cloned a previously undescribed adhesion molecule, VCAM-1, which is induced by cytokines on human endothelial cells and binds lymphocytes. Using a novel method requiring neither monoclonal antibodies nor purified protein, VCAM-1-expressing clones were selected by adhesion to human lymphoid cell lines. VCAM-1 mRNA is present in endothelial cells at 2 hr after treatment with IL-1 or TNF-alpha and is maintained for at least 72 hr; leukocyte binding activity parallels mRNA induction. Cells transfected with VCAM-1 bind the human leukemia lines Jurkat, Ramos, Raji, HL60, and THP1, but not peripheral blood neutrophils. VCAM-1, which belongs to the immunoglobulin gene super-family, may be central to recruitment of mononuclear leukocytes into inflammatory sites in vivo.
Tumor necrosis factor (TNF) is a monocyte-derived cytotoxin that has been implicated in tumor regression, septic shock, and cachexia. The mechanism by which TNF induces these different disease states is unclear. We have identified and characterized a novel, rapidly inducible cell surface cytotoxic integral transmembrane form of TNF. The existence and behavior of this novel form of TNF may explain the complex physiology of this molecule. We suggest that activated monocytes synthesize transmembrane TNF at the site of inflammation and kill their targets by either cell-to-cell contact or local release of the TNF secretory component. In contrast, septic shock and cachexia may result from either acute or chronic systemic activation of monocytes, resulting in the widespread release of TNF secretory component into the circulation of the affected individual. We further suggest that cell borne cytokines and cytotoxins may be the primary mediators of directed inflammatory responses.
To better understand local migration of inflammatory cells in psoriasis, we compared immunohistochemically the expression of cell adhesion molecules on endothelial cells of papillary microvessels, a subpapillary microvessel (SPMV), with the phenotypic profile of infiltrating T cells in initial, active, and involuting psoriatic lesions.
Intercellular adhesion molecule-1, E-selectin, and vascular cell adhesion molecule-1 (VCAM-1) on papillary microvessel E-selectin and VCAM-1 on SPMV that had not been detected in normal/noninvolved skin were induced in psoriatic lesions. Intercellular adhesion molecule-1 on SPMV was constitutively expressed in normal/noninvolved skin and augmented in the degree of expression in psoriatic lesions. Intraepidermal and dermal angiocentric T cells in the initial and active lesions belonged predominantly to the CD3+, CD4+, CD45RO+, lymphocyte function-associated antigen-1+, and very late antigen-4+ helper-inducer/memory subset. The number of these memory T cells around SPMV was significantly correlated with the degree of expression of E-selectin and VCAM-1 on SPMV in the initial lesion. Intraepidermal memory T cells in the active lesion showed significant correlation with the expression of E-selectin and VCAM-1 on PMV. The CD8+ cells were dominant in the epidermis of the involuting phase. None of the adhesion molecules studied seemed to play a role in infiltration of this cell type.
The results suggest (1) participation of memory T cells in the formation of the initial and active stages of psoriatic plaques, and (2) E-selectin and VCAM-1 on endothelium as the critical adhesion molecule for initial trafficking of memory T cells into psoriatic lesions.
Tumour necrosis factor alpha (TNF-alpha) is a potent immunoregulatory cytokine produced by many cutaneous cells, including keratinocytes, mast cells and Langerhans cells. To explore its potential role in inflammatory skin disease, we have studied immunohistochemically the effects of intradermal recombinant human TNF-alpha (rHuTNF-alpha) on cutaneous inflammatory cells, adhesion molecules and Langerhans cells in normal human skin. Volunteers receive rHuTNF-alpha 100 U (group A), 5000 U (group B), or 100 U daily for 5 days (group C), and biopsies were taken at 6 h (groups A and B), or 6 h after the final injection (group C). An inflammatory cell infiltrate developed in all cases: following single injections of either 100 or 5000 U rHuTNF-alpha this was predominantly neutrophilic, whereas following multiple injections of 100 U few neutrophils were seen, although many lymphocytes (CD3+, CD4+) were present. In all groups there was an increase in cells of monocyte/macrophage lineage (CD36+). TNF-alpha induced a dose- and time-dependent decrease in CD1a+ epidermal Langerhans cell numbers and an increase in dermal CD1a+ cells, suggesting migration of Langerhans cells away from the epidermis. TNF-alpha induced endothelial E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in all groups, and adhesion molecule expression by interstitial dermal dendritic cells (ICAM-1 and VCAM-1) and keratinocytes (ICAM-1) was observed. These findings indicate that TNF-alpha is a potent modulator of cutaneous immune function in vivo, and this central role in the cutaneous immune response suggests that TNF-alpha may be an attractive target for therapeutic inhibition.
Psoriasis is a hyperproliferative and inflammatory skin disorder of unknown aetiology. A fusion protein composed of human interleukin-2 and fragments of diphtheria toxin (DAB389IL-2), which selectively blocks the growth of activated lymphocytes but not keratinocytes, was administered systemically to ten patients to gauge the contribution of activated T cells to the disease. Four patients showed striking clinical improvement and four moderate improvement, after two cycle of low dose IL-2-toxin. The reversal of several molecular markers of epidermal dysfunction was associated with a marked reduction in intraepidermal CD3+ and CD8+ T cells, suggesting a primary immunological basis for this widespread disorder.
Results of clinical trials have indicated that cA2, a neutralizing mouse/human IgG1 chimeric anti-human TNF-alpha monoclonal antibody, may have therapeutic benefit for rheumatoid arthritis patients. Arthritic joints contain, in addition to elevated levels of soluble TNF-alpha, high numbers of CD4+ T cells and macrophages, cells known to express transmembrane TNF-alpha upon activation. For that reason, we sought to determine if cA2 binds to transmembrane TNF-alpha and what effects such binding may have on TNF-alpha-expressing cells. A cell line expressing a cell-surface, mutant form of transmembrane TNF-alpha was prepared for these studies. Analysis of these TNF+ cells by flow cytometry, direct binding, and competitive binding assays showed that cA2 binds to the transmembrane form of TNF-alpha with high avidity. Binding of the IgG1 isotype of cA2, but not an IgG4 version of cA2, resulted in efficient killing of the TNF+ cells by both antibody-dependent cellular toxicity and complement-dependent cytotoxicity effector mechanisms. These findings indicate that, in addition to blocking soluble TNF-alpha activity, cA2 can bind to transmembrane TNF-alpha in vitro and suggest that cA2 binding may lead to lysis of TNF-alpha-expressing cells in vivo.
Two subfamilies of chemokines are distinguished depending on the arrangement of the first two of four conserved cysteines, which are either separated by one amino acid (CXC chemokines) or adjacent (CC chemokines). IL-8 and the other CXC chemokines act preferentially on neutrophils, while the CC chemokines (MCP-1, MCP-2, MCP-3, RANTES, MIP-1 alpha and MIP-1 beta) act on monocytes, but not neutrophils, and have additional activities toward basophil and eosinophil granulocytes, and T-lymphocytes. Several chemokine receptors have been identified, all of which belong to the seven-transmembrane-domain type and are coupled to G-proteins. The discovery of chemokines has provided the basis for the understanding of leukocyte recruitment and activation in inflammation and other disturbances of tissue homeostasis.
To define the immunohistologic features of the synovial membrane (SM) of patients with psoriatic arthritis (PA) and to compare them with those of an age- and disease-duration-matched population of patients with rheumatoid arthritis (RA).
Synovial membrane needle biopsy was performed on 15 PA patients with knee involvement (8 had asymmetric oligoarthritis and 7 had symmetric polyarthritis) and on 15 RA controls. Specimens were stained with monoclonal antibodies against T cells (CD3, CD8, CD4, CD45RO), B cells (CD20), macrophages (Mac387, CD14), and cells bearing class II antigens (DAKO-DR). Vascular endothelium was examined using a polyclonal antibody to Factor VIII-related antigen, and adhesion molecule expression was examined using antibodies 1.3B6, 6.5B5, and 1.4C3, which identify endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1), respectively.
There was significantly less lining layer hyperplasia, fewer macrophages, and a greater number of blood vessels in PA SM than in RA SM: ELAM-1 expression was less intense in PA than in RA SM, while there was no difference in expression of ICAM-1 and VCAM-1. Numbers of B cells, T cells, and T cell subsets (predominantly CD4, CD45RO T cells) were similar in both groups of patients.
Our findings demonstrate important differences in the immunohistologic features of PA and RA SM: The PA SM is more vascular, ELAM-1 expression is less intense, and fewer macrophages invade the stroma and migrate to the lining layer than in RA SM: However, the lymphocytic infiltrate in the SM of both groups is similar.
Involvement of various cytokines in psoriasis pathomechanisms has previously been reported.
To better define the relationship between the disease severity and interleukin-6 and tumour necrosis factor alpha skin levels, these two cytokines were measured in suction blister fluids obtained from involved and uninvolved skin areas of psoriatic patients treated with UVB, beta-methasone dipropionate and salicylic acid ointment.
Determinations were performed by ELISA in fluids obtained from 6 patients with the Kiistala method, every 1-2 weeks for at least 1 month.
During the observation period, all the patients showed disease improvement (median PASI score declined from 13.4 to 3.9) and significant decreases in the cytokine levels in all samples.
These results are in agreement with a functional involvement of these two cytokines in the pathogenesis of the disease and their possible use as follow-up markers.
Tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and granulocyte monocyte-colony stimulating factor (GM-CSF) were measured in serum and involved and uninvolved skin blister fluids of 20 psoriatic patients and 10 healthy subjects, by enzyme immunoassay. TNF-alpha and IL-6 were always detectable in involved skin blister fluids, while GM-CSF was detected only in 45% of these samples. TNF-alpha, IL-6 and GM-CSF were detected in 95, 100 and 10% of uninvolved skin blister fluid samples, respectively. TNF-alpha and IL-6 were found in 50 and 30% of control blister fluids, while GM-CSF was never detected. In serum, TNF-alpha was detected in 75% of patients and in 70% of controls; IL-6 in 45% of patients and in no controls; and GM-CSF in 35% of patients and in 20% of the controls. The median TNF-alpha and IL-6 levels in involved skin were statistically higher than those of both uninvolved and control skin blister fluids. TNF-alpha and IL-6 levels in blister fluids obtained from both involved and uninvolved skin were higher than those of the patients' sera. GM-CSF, when present in involved skin blister fluids, showed correlated levels with the other cytokines (TNF-alpha: R = 0.85, P = 0.004; IL-6: R = 0.72, P = 0.03). TNF-alpha was highly correlated with IL-6 (R = 0.78, P < 0.00001) in involved skin blister fluids. TNF-alpha and IL-6 levels of involved skin blister fluids showed significant correlations with the psoriasis area and severity index scores in the patients, suggesting a direct relationship between these cytokines and the clinical manifestations of the disease. Moreover, the TNF-alpha levels were particularly related to the erythema scores in the patients, further supporting evidence of their role in the pathogenesis of the disease.
We recently reported that polyclonal anti-CD3 epsilon-pulsed Th2 cells mediate local tissue inflammation (DTH2) when injected into naive syngenic recipient mice, and that this response is entirely dependent on IL-4 in BALB/c (H-2d) mice. We now describe a different cytokine dependence in mice that bear a H-2b MHC haplotype. Injection of either soluble IL-4R (sIL-4R) or anti-TNF Ab partially inhibited swelling that was mediated by Th2 cells from high TNF-producing C57BL/6 mice. Anti-TNF and sIL-4R in combination were required to completely abrogate the swelling reaction and cellular infiltrate. Adoptive transfers across strain barriers showed that the TNF dependence was dictated by the origin of the transferred cells, rather than by the recipient. Experiments with intra-H-2 recombinant C57BL/10 strains indicated that TNF released by Th2 cells was correlated with the involvement of TNF in DTH2: Th2 cells from the H-2Db strains C57BL/10 and B10.A(2R) produced high amounts of bioactive TNF and mediated swelling that was partially inhibited by anti-TNF. In contrast, Th2 cells from B10.D2 and B10.A mice (H-2Dd) produced low levels of TNF, and anti-TNF had no effect on DTH2 in these strains. Our results suggest a linkage between the TNF dependence of DTH2, the capacity of Th2 cells to release TNF upon restimulation, and the donor H-2D haplotype; strain-dependent allelic expression of TNF seems to determine the involvement of this cytokine in DTH2.
To investigate whether growth factors derived from T cells in psoriatic lesions are able to stimulate keratinocyte growth, T-cell lines were initiated from lesional psoriasis skin and cloned by limiting dilution. Eight clones with good proliferative capacity out of 40 clones from one patient were stimulated. After 24 h, the conditioned medium was harvested and the growth modulatory effect of the conditioned medium on keratinocytes was assessed. Seven of the eight T-cell clones stimulated keratinocyte growth to an extent ranging from 22% ± 19 to 64% ± 9 (mean ± SD of three experiments) of maximal inducible keratinocyte growth, and one T-cell clone had no effect (-5% ± 2) on keratinocyte growth. Keratinocyte growth was also induced by T-cell clones obtained from two other patients.
Several cytokines were tested in this system to determine which T-cell growth factor may induce the keratinocyte growth. None of the cytokines interferon-g, transforming growth factor-β, interleukin (IL)-2, IL-3, IL-4, IL-6, IL-8, or granulocyte-macrophage colony stimulating factor alone was found to possibly be responsible for the T-cell – induced keratinocyte growth. Thus the nature of the T-cell keratinocyte growth-promoting stimulus remains to be elucidated.
Delayed-type hypersensitivity and allograft rejection are dependent upon the generation of Ag-specific T cell immune responses. The mixed lymphocyte reaction is a model of alloantigen-driven immunity and has provided significant insight into the mechanisms of T cell proliferation. Recently, soluble mediators, including TNF-alpha have been shown to be involved in the full expression of this response. In order to elucidate the potential mechanisms of cellular recruitment in the context of either delayed-type hypersensitivity or allograft rejection, we employed a mixed lymphocyte reaction to study the production of chemokines, monocyte chemoattractant protein-1 (MCP-1), and IL-8. Time-course experiments demonstrated that significant levels of MCP-1 and IL-8 were produced in allogeneic cultures as early as day 1, and that this relationship persisted over 6 days in culture. Northern blot analysis of chemokine mRNA confirmed the early induction of these genes in the allogeneic response. The levels of MCP-1 and IL-8 protein from mixed lymphocyte reaction supernatants as measured by specific ELISA were positively correlated with the proliferative response as measured by [3H]TdR uptake. Although significant MCP-1 and IL-8 were produced during a mixed lymphocyte reaction, these molecules did not participate in the proliferative response, as neutralizing antibodies to either MCP-1 or IL-8 had no effect on proliferation. In order to ascertain the mechanism for the induction of MCP-1 and IL-8 during the mixed lymphocyte reaction, experiments were performed in the presence of neutralizing anti-human TNF antibodies. Neutralization of TNF resulted in significant abrogation of MCP-1 and IL-8 production (75 +/- 5 and 87 +/- 2 percent, respectively). Cells isolated from the mixed lymphocyte reaction at day 6, demonstrated that MCP-1 and IL-8 Ag were localized to mononuclear phagocytes. These results demonstrate that potent chemokines, MCP-1 and IL-8, are produced during the evolution of a mixed lymphocyte reaction, and their induction is TNF-dependent.
Epidermal cell proliferation is required for re-epithelialization during wound repair. Re-epithelialization of partial thickness excisional wounds in pigs is complete by 6 days after injury. The presence of insulin-like growth factor-I (IGF-I) and heparin-binding molecules that are mitogenic for keratinocytes was examined in wound fluid obtained daily from these wounds. Two significant heparin-binding growth factor activities for Balb/MK keratinocytes were detected, a major one that was eluted from a heparin affinity column with 1.1 M NaCl and a minor one with 0.5 M NaCl. These activities appeared 1 day after injury, were maximal by 2-3 days later, and disappeared by 6 days after injury. The molecule eluting with 1.1 M NaCl was heparin-binding EGF-like (HB-EGF). The levels of IGF-I in wound fluid were 45-90 ng/ml during the first 3 days following injury, decreased thereafter, and were not detectable 6 days after injury. IGF-I at 100 ng/ml, increased HB-EGF mitogenic activity for Balb/MK keratinocytes by 40-50 fold. We conclude that the synergism between IGF-I and HB-EGF and their relative concentration at the various days after injury may be important variables for regulating re-epithelialization during wound repair.
Psoriatic fibroblasts produce enhanced amounts of IL-6 in vitro. This state of activation may reflect an altered expression of cytokine receptors, involved in auto/paracrine induction of IL-6. Cultures of dermal fibroblasts derived from lesional psoriatic (PP) and normal control (NN) skin were therefore analysed for their ability to bind biotinylated recombinant human cytokines using flow cytometry. PP and NN fibroblasts bound negligible amounts of IL-1 alpha and IL-1 beta, but clearly bound IL-4, IL-6 and TNF-alpha. Serum upregulated the number of NN fibroblasts which bound TNF-alpha, and to a lesser extent IL-6, but not the number of binding sites per cell. In contrast, this upregulation was significantly less in PP fibroblasts. This was not a result of differences in growth characteristics, receptor occupancy or an inability of stimulated PP fibroblasts to bind TNF-alpha. Immunocytochemistry of cells grown on slides showed that the TNF receptor type 1 (TNFR1, p55) was the predominant receptor in NN fibroblasts and was localized to the nucleus of cytoplasma. The expression of TNFR1 was clearly decreased in PP fibroblasts, which confirmed the binding studies. A slow and serum-induced shedding of TNFR1 was observed, but not of the TNFR2 (p75), in both types of fibroblasts. Confluent multi-passaged PP fibroblasts display both a decreased TNFR expression as well as an enhanced IL-6 production under serum conditions. These inherent abnormalities of PP fibroblasts imply the involvement of dermal fibroblasts in the maintenance of chronic inflammation in psoriasis.
Activated T lymphocytes are thought to be involved in the pathogenesis of psoriasis. From studies with peripheral blood T lymphocytes it is known that T cells show a decrease in membrane expression of CD27 molecules during continuous antigenic stimulation. The T-cell activation molecule CD28 is thought to be involved in the transduction of an antigen-non-specific costimulatory signal. Therefore, in order to elucidate further the pathogenesis of psoriasis we studied the expression of CD27 and CD28, together with CD4, CD8 and CD45RA in this benign inflammatory dermatological disease. We used immunohistochemical techniques to determine absolute numbers of T lymphocytes and expression of these T-cell activation and T-subset-specific molecules in normal (n = 7), uninvolved perilesional (n = 7) and lesional psoriatic (n = 7) skin. We found that not only lesional but also clinically uninvolved perilesional skin showed an increased number of T cells. Further, immunohistochemical studies showed that CD27 is expressed by a minority of normal skin T cells, while in lesional psoriatic skin, expression was even lower, and almost absent in perilesional skin sections. In contrast to normal skin, both perilesional and lesional psoriatic skin contained no CD28 positive T cells. In lesional psoriatic skin, however, T cells showed predominantly the CD4 phenotype, while in perilesional skin CD8 positive T cells were dominant. Two conclusions were reached: first, the absolute number of T cells, their CD27, CD28 and CD45RA expression, and the influx of CD8 positive T cells, indicate that perilesional psoriatic skin is different from normal and lesional psoriatic skin; and secondly, the data on CD27 and CD28 suggest that not only lesional but also perilesional psoriatic skin is subject to continuous antigenic stimulation, thus leading to decreased CD27 and CD28 expression on skin T cells.
Establishing direct and causal relationships among the confederacy of activated cell types present in psoriasis has been hampered by lack of an animal model. Within psoriatic plaques there are hyperplastic keratinocytes, infiltrating immunocytes, and activated endothelial cells. The purpose of this study was to determine if psoriasis is primarily a disorder of keratinocytes or the immune system. Using a newly developed experimental system in which full-thickness human skin is orthotopically transferred onto severe combined immunodeficient mice, autologous immunocytes were injected into dermis, and the resultant phenotype characterized by clinical, histologic, and immunophenotypic analyses. Engraftment of samples included both uninvolved/ symptomless (PN) skin removed from patients with psoriasis elsewhere, or from healthy individuals with no skin disease (NN skin). In 10 different experiments involving 6 different psoriasis patients, every PN skin was converted to a full-fledged psoriatic plaque skin by injection of autologous blood-derived immunocytes. In all but one psoriatic patient, the immunocytes required preactivation with IL-2 and superantigens to convert PN skin into psoriatic plaque skin. In every case, resultant plaques were characterized by visible presence of flaking and thickened skin, loss of the granular cell layer, prominent elongation of rete pegs with a dermal angiogenic tissue reaction, and infiltration within the epidermis by T cells. Lesional skin displayed 20 different antigenic determinants of the psoriatic phenotype. None of the four NN skin samples injected with autologous immunocytes converted to psoriatic plaques. We conclude that psoriasis is caused primarily by the ability of pathogenetic blood-derived immunocytes to induce secondary activation and disordered growth of endogenous cutaneous cells including keratinocytes and vascular endothelium.
To evaluate the immunological function of peripheral blood monocytes (PBMC) in psoriasis, we measured spontaneous production of the inflammatory cytokines, TNF-alpha, IL-1beta and IL-6 from the PBMC of psoriasis patients, by enzyme linked immunosorbent assay (ELISA). The production of all three inflammatory cytokines by psoriatic PBMC was significantly higher than that by normal control PBMC. PBMC sampled from active psoriasis produced three cytokines significantly higher than samples from inactive psoriasis. In addition, IL-1beta and TNF-alpha production showed a positive relation to clinical severity, but IL-6 did not. TNF-alpha production increased much more than did the others. Therefore, the TNF-alpha to IL-1beta ratio was significantly higher, even in inactive psoriasis, than that of the normal control. In relation to focal infection, psoriatic PBMC sampled 3 h after a tonsillar provocation test increased cytokine production, compared with the level before provocation. The cases which responded to tonsillectomy or systemic methotrexate therapy, but not the non-responding cases, showed a significant decrease in PBMC cytokine productivity. These results strongly suggest that inflammatory cytokines, especially TNF-alpha, from monocytes are involved in the pathogenesis of psoriasis, and activated monocytes may work as an effective mediator of focal infection in skin lesions.
Psoriatic arthritis is an inflammatory arthropathy that ultimately can lead to joint destruction. In this study, we investigated the immunophenotypes of the inflammatory cells and the expression of interleukin-8 (IL-8), which is the hallmark chemoattractant cytokine of psoriasis in synovial membranes from patients exhibiting active psoriatic synovitis (n = 9). The tissue samples were examined by immunohistochemistry, Western blot analysis and in situ hybridisation. The inflammatory infiltrate consisted predominantly of CD3+ T lymphocytes, with a higher proportion of CD4+ than CD8+ T lymphocytes in six cases. CD3+ T lymphocytes were focally distributed near small blood vessels and the enlarged synovial intima. CD1+ interdigitating reticulum cells were not detected. CD22+ B lymphocytes and plasma cells were found in small aggregates without KiM4+ follicular dendritic cells. KiM8+ macrophages were located in the synovial intima and were distributed in a diffuse pattern near the synovial lining cells. CD15+ neutrophil granulocytes were detected in four cases. They were preferentially located in the vicinity of blood vessels and the synovial intima. IL-8 was found at a high level in the synovial lining cells and to a lesser extent in cells located in the perivascular areas. Immunofluorescence double staining showed IL-8 to be expressed in KiM8+ multinucleated giant cells, KiM8+ macrophages and CD3+ T lymphocytes. IL-8 receptor A was demonstrated in the synovial lining and in macrophages and lymphocytes. IL-8 was detected by immunoblot analysis of the synovial tissue at 8.4 kD. Employing in situ hybridisation, IL-8 mRNA was strongly and preferentially expressed in the synovial intima, as well as in macrophages and lymphocytes. The immunophenotype of the psoriatic arthritis inflammatory cells shows great similarity to the inflammatory infiltrate found in the synovial tissue of patients with rheumatoid arthritis. The preferential expression of IL-8 and IL-8 mRNA in the enlarged synovial intima and in lymphocytes and macrophages suggests that IL-8 exerts its action through activated mononuclear cells and T lymphocytes. It seems to play a role in regulating leucocyte traffic into the enlarged synovial intima and may contribute to the aggressive synovitis of patients with psoriatic arthritis.
Epidermal growth factor (EGF) family members and its receptor (EGFR) are thought to have an important role in the proliferation of epidermal keratinocytes. In this report, we investigated the EGF/EGFR system in primary keratinocytes derived from normal and psoriatic lesional skin. EGF elicited the growth of both normal human keratinocytes (NHKs) and psoriatic lesional keratinocytes (PLKs). Interleukin-6 (IL-6) potentiated the EGF-dependent growth of NHKs, but has no observable effect on PLKs, while IL-6 itself showed no growth-stimulating activities in both cell types. Immunodetection and in situ hybridization analyses revealed that IL-6 induces EGFR expression in NHKs in a time- and dose-dependent manner. This EGFR expression decreased reversibly to an undetectable level when IL-6-treated NHKs were re-cultured in IL-6-free conditions. On the other hand, PLKs expressed high levels of EGFR even when unstimulated and the expression level was not affected by IL-6 stimulation. These results suggest that the EGF/EGFR system is involved in the growth of NHKs and PLKs and that IL-6 potentiates NHK growth partly through the induction of EGFR. The different EGFR regulatory system may contribute to the pathogenesis of psoriasis.
Soluble tumor necrosis factor (TNF) receptor fusion protein (p75) (Enbrel) is a reversible inhibitor of the biologic effects of TNF. Enbrel has been shown in placebo-controlled trials to significantly improve the signs and symptoms of rheumatoid arthritis. Clinical trials are now in progress to assess the safety and efficacy of Enbrel in combination with methotrexate in refractory rheumatoid arthritis along with trials to compare Enbrel to methotrexate in patients with early rheumatoid arthritis.
In vivo cell-mediated immune reactions are characterized by mixtures of monocytes and T cells. The purpose of this study was to investigate the role of monocytes on T-cell migration and induction of endothelial adhesion molecules. The in vitro model consisted of adding peripheral blood mononuclear cells (PBMC), T cells or mixtures of monocytes and T cells, to endothelial cells on a porous membrane and using flow cytometry to distinguish between the monocyte and lymphocyte components. PBMC and PBMC supernatants were highly potent at upregulating intercellular adhesion molecule-1 (ICAM-1) and inducing expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Induction by supernatants was inhibited by antibodies to tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL)-1 beta. Using monocyte-enriched populations, as few as one monocyte to 100 endothelial cells was sufficient to upregulate adhesion molecules. Fixed monocytes also induced adhesion molecules and expressed surface-bound cytokines. In contrast, highly purified unstimulated T cells were not found to induce adhesion molecules at 4, 6, 24 or 48 hr of coculture. Purified T cells showed low-level migration through resting (VCAM-1 negative) endothelium, which was approximately doubled by addition of small numbers of monocytes or TNF-alpha. In conclusion, monocytes, via cell surface or released cytokines play an essential role in allowing large-scale recruitment of T cells to inflammatory sites in vivo.
The release of cytokines from cutaneous cells may be of major importance in the initiation and development of many inflammatory skin disorders. For example, tumor necrosis factor-alpha (TNF-alpha), which in healthy skin is found preformed only in mast cells, is able to induce the expression of several adhesion molecules including intercellular adhesion molecule-1 (ICAM-1). Increased expression of ICAM-1 occurs in keratinocytes in lesional skin of psoriasis and atopic dermatitis (AD) and it is considered to be an important initiator of leucocyte/keratinocyte interactions in skin inflammation. We counted the mast cells showing TNF-alpha immunoreactivity using a double-staining method in nonlesional and lesional skin sections from 12 patients with AD and 12 patients with psoriasis. The percentage of TNF-alpha+ mast cells in lesional and nonlesional AD skin was 36 +/- 22% and 21 +/- 15% (P < 0.018, paired t-test), respectively, and in psoriatic skin was 16 +/- 25% and 15 +/- 15%, respectively (P < 0.89, paired t-test). We also cultured whole skin biopsies taken from the healthy-looking skin of psoriatic and AD patients in the presence of mast cell degranulator compound 48/80, which resulted in focal expression of ICAM-1 in the epidermis. In cultured keratinocytes, both histamine and an extract of a human mast-cell line (HMC-1) induced ICAM-1 immunostaining only in occasional cells, but the combination of histamine and the HMC-1 extract resulted in intense ICAM-1 staining in numerous cells. This enhancement of ICAM-1 staining was abolished by preincubation of the HMC-1 extract with anti-TNF-alpha antibody. These results suggest that the degranulation of mast cells induces the expression of ICAM-1 in keratinocytes probably via TNF-alpha and histamine.
During the early aspecific phase of host defense, production of interferon (IFN)‐γ by natural killer cells plays an important role in bringing about acute inflammation, mainly because of the activating effects of IFN‐γ on adhesive properties of endothelial cells and on mediator production by mononuclear phagocytes (MPCs). In the subsequent antigen‐specific phase of the immune response, IFN‐γ acts as a regulator of antigen presentation and of proliferation and differentiation of lymphocyte populations. Immunosuppressive as well as immunostimulatory effects may result from these actions.
High‐level production of IFN‐γ during this phase of host defense is now classically seen as a hallmark of a T‐helper 1 (TH1)‐type reaction, characterized by activation of antimicrobial activity of macrophages and by inflammatory reactions with a DTH character. Development of TH1‐type lymphocyte populations producing IFN‐γ is regulated by other cytokines including interleukin (IL)‐12. In many systems IL‐12 and IFN‐γ act in a similar fashion, and a current subject of debate is the question of whether all activities of IL‐12 are mediated by IFN‐γ. Another question is whether IFN‐γ, by its ability to potentiate MPCs' ability to produce IL‐12, plays a role in bringing about or stabilizing TH1 type responses. In two model systems of autoimmune disease, experimental autoimmune encephalomyelitis and collagen‐induced arthritis, IL‐12 and IFN‐γ were found to act independently.
Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate.
In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks.
The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept.
In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.
To determine the expression of tumor necrosis factor (TNF) receptor in patients with systemic inflammatory response syndrome (SIRS).
Prospective study.
Intensive care unit and central laboratory.
Blood specimens from 18 healthy volunteers (controls) and 16 patients with SIRS.
None.
Using monoclonal antibodies, fluorescence labeling, and high sensitivity flow cytometry, we measured the expression of membrane TNF receptor subtypes TNF-R55 and TNF-R75 on peripheral blood leukocytes. Receptor expression is expressed as mean fluorescence intensity +/- SD (units: detection channel number). In controls, TNF-R55 was only weakly expressed (monocytes: 2.5+/-1.8; neutrophils: 0.7+/-0.8), whereas expression of TNF-R75 was higher (monocytes: 28.6+/-9.0; neutrophils: 4.8+/-1.0) and was also found on lymphocytes (on CD8+ lymphocytes: 5.7+/-1.8; CD16+: 5.5+/-1.2; CD4+: 9.7+/-3.7). In SIRS, we observed increased expression of TNF-R55 on monocytes (6.9+/-3.4, p<.001) and neutrophils (2.2+/-1.9, p<.01), as well as decreased expression of TNF-R75 on monocytes (17.3+/-13.2; p<.001). The extent of TNF-R55 up-regulation did not correlate with that of TNF-R75 down-regulation. TNF-R55 on monocytes and neutrophils strongly correlated with body temperature but not with survival, whereas monocyte TNF-R75 was considerably lower in nonsurvivors, albeit not significantly (12.3+/-7.1 vs. 23.9+/-16.7; p = .07).
These data indicate that leukocyte TNF-R55 and TNF-R75 react differentially and probably serve different functions in SIRS, which prompts the investigation of receptor subtype-specific therapeutic approaches.
Infliximab and etanercept, both approved by the FDA in 1998, are examples of a new class of disease-modifying antirheumatic drugs that interfere with the action of tumor necrosis factor alpha, one of the key cytokines that promote inflammation. Infliximab is approved for Crohn disease and etanercept for rheumatoid arthritis. Both show promise in treating rheumatoid arthritis, although the long-term risks and benefits of these drugs are not yet known.
Psoriasis is an immunologically mediated skin disease linked to several different class I major histocompatibility complex alleles. However, the phenotype of the pathogenic lymphocyte and nature of the T cell activating event which triggers conversion of symptomless (PN) skin into psoriatic plaques (PP skin) is unknown. This study extends our previous observations in which autologous blood-derived immunocytes were injected into PN skin engrafted onto SCID mice to produce full-fledged PP lesions. The first question addressed is whether injected CD4+ T cells or CD8+ T cells were responsible for phenotypic conversion of PN to PP skin. In five different patients only CD4+ but not CD8+ T cell lines produced psoriatic lesions. Next, immunological events occurring within PN skin following injection of CD4+ T cells in grafts that had sufficient tissue available for detailed analysis was examined. In two patients, intraepidermal resident CD8+ T cells were induced to proliferate during lesion development, expressing acute activation markers CD25 and CD69. In another patient, injection of CD4+ T cells revealed CD69 expression by intraepidermal CD4+ as well as CD8+ T cells. To explore the molecular basis for local T cell activation and proliferation, we discovered that intraepidermal immunocytes, including both CD4 and CD8+ T cells, expressed surface receptors (ie, CD94, CD158a, CD158b) typically confined to natural killer cells (ie, natural killer receptors; NKRs) accumulated immediately before onset of acute lesions. The presence of NKR bearing immunocytes was also observed in 10 of 15 different biopsies of chronic plaques taken directly from patients, whereas PN skin (n = 8) or normal skin from healthy donors (n = 8), did not contain such NKR positive immunocytes. Of particular relevance to psoriasis is that these NKRs recognize various class I alleles including those typically inherited by psoriatic family members such as HLA-C and HLA-B allotypes. We conclude that injection of CD4+ T cells into PN skin triggers a series of local immunologically mediated stimulatory events that produce further T cell activation and appearance of both CD4 and CD8+ T cells that express NKRs.
A consistent feature of chronic leg and pressure ulcers is chronic inflammation associated with an elevated infiltration of neutrophils. Neutrophils and their proteases have been implicated in mediating the tissue damage associated with a variety of chronic inflammatory diseases. This review discusses our current understanding of the proteolytic enzymes found in chronic wounds and attempts to relate this information to the abundant presence of neutrophils. In addition, the implications that the proteolytic environment may have for current and future treatment strategies of chronic nonhealing wounds are discussed.
We studied the effects of the cytokines IL-1alpha, IL-6, tumour necrosis factor-alpha (TNF-alpha), IL-4, IL-10, IL-13 and transforming growth factor-beta (TGF-beta) on fibronectin (FN) production by cultured-human monocytes. IL-1alpha, IL-6 and TNF-alpha all increased FN production, an indicator of monocyte activation. These cytokines increased FN production in a dose-dependent fashion, with a 4-h treatment being sufficient to measure FN production by radioimmunoassay. Conversely, IL-4, IL-10 and IL-13 strongly inhibited cytokine-induced FN production, while TGF-beta only partially inhibited FN production. The combination of suboptimal doses of cytokines (IL-1alpha + IL-6, IL-1alpha + TNF-alpha, IL-6 + TNF-alpha), which could not singly induce substantial amounts of FN, were able to induce FN production by cultured monocytes. Northern blot analysis with a cDNA specific for FN confirmed the expression of FN mRNA in cultured monocytes stimulated with a single cytokine or a combination of cytokines. Our data demonstrate that monocytes may not always require high concentrations of cytokines for activation in vitro, and that the synergistic or additive action of low levels of cytokines on monocyte activation may be sufficient to promote immune or inflammatory reactions. Our data also suggest that certain T cell cytokines may regulate monocyte activation.
Etanercept, a tumour-necrosis-factor inhibitor, has shown efficacy in the treatment of rheumatoid arthritis. Psoriatic arthritis and psoriasis are disease states in which tumour necrosis factor, a proinflammatory cytokine, is present in increased concentrations in joints and in the skin. Therefore, psoriatic arthritis and psoriasis may be appropriate therapeutic targets for etanercept.
This randomised, double-blind, placebo-controlled, 12 week study assessed the efficacy and safety of etanercept (25 mg twice-weekly subcutaneous injections) or placebo in 60 patients with psoriatic arthritis and psoriasis. Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria (PsARC) and who met the American College of Rheumatology preliminary criteria for improvement (ACR20). Psoriasis endpoints included improvement in the psoriasis area and severity index (PASI) and improvement in prospectively-identified individual target lesions.
In this 12 week study, 26 (87%) of etanercept-treated patients met the PsARC, compared with seven (23%) of placebo-controlled patients. The ARC20 was achieved by 22 (73%) of etanercept-treated patients compared with four (13%) of placebo-treated patients. Of the 19 patients in each treatment group who could be assessed for psoriasis (> or = 3% body surface area), five (26%) of etanercept-treated patients achieved a 75% improvement in the PASI, compared with none of the placebo-treated patients (p=0.015). The median PASI improvement was 46% in etanercept-treated patients versus 9% in placebo-treated patients; similarly, median target lesion improvements were 50% and 0, respectively. Etanercept was well tolerated.
Etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease.
Serum pro- and anti-inflammatory mediators in patients with acute liver diseases were assessed to clarify the clinical significance
of these measurements in relation to disease severity. Concentrations of circulating tumor necrosis factor (TNF)—α, interleukin
(IL)—1β, IL-6, IL- 10, IL-12, and soluble TNF receptors (sTNFR) p55 and p75 were measured at admission in patients with fulminant
hepatitis (FH; n = 19), severe acute hepatitis (AHS, n = 15), or acute hepatitis (AH, n = 7). Serum concentrations of TNF-α, IL-10, and sTNFR-55 were significantly higher in patients with FH than in those with
AHS (P< .05 < .05, and < .01, respectively) or AH (P < .05). Serum IL-10 and TNF-α levels were higher in patients who died of FH (n = 13) than in FH survivors (n = 6; P<.05). The ratios between TNF-α and IL-10 and sTNFR-55 or sTNFR-75 were not valuable in predicting mortality and disease severity.
However, both proinflammatory cytokine TNF-α and anti-inflammatory cytokine IL-10 levels at admission were associated with
fatal outcome among patients with FH.
To examine normal and psoriatic skin and synovial tissue from patients with psoriatic arthritis (PsA) for evidence of monocyte chemotactic protein-1 (MCP-1) mediated T cell chemotaxis.
Peripheral blood (PB), synovial fluid (SF), normal and psoriatic skin, and synovial biopsies were obtained from patients with PsA (n = 19) and compared to samples from normal (n = 5) and disease (n = 5) controls (NC, DC). Immune cell populations in PB and SF samples were assessed by immunofluorescent labeling and flow cytometry, levels of soluble MCP-1 were determined by quantitative ELISA, and immunohistochemistry was used to detect T cell subsets and macrophages and MCP-1 protein in frozen skin and synovial tissue sections.
CD8+ but not CD4+ T cells were elevated in SF compared to PB, and the majority of these cells expressed CD45RO. Plasma MCP-1 levels in PsA were elevated relative to NC. MCP-1 levels were significantly higher than paired plasma samples in patients with recent onset (< 6 mo) synovitis (n = 10). A positive correlation was observed between synovial T cell numbers and MCP-1 levels in SF. MCP-1 protein was present in all tissues examined, but most intense expression was observed in synovium.
Elevated concentrations of MCP-1 concomitant with memory T cell infiltration in PsA SF suggests that MCP-1 mediated chemotaxis is involved in the recruitment of T lymphocytes into the synovial compartment of patients with PsA.
Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known.
We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically.
The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response.
In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.