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Tofacitinib treatment reverses immune-mediated kidney damage in MRL/lpr mice. Representative H&E stained kidney sections of mice described in Fig. 2a. Magnification, 100×. The extent of glomerular hypercellularity, mesangial expansion, crescent formation, fibrinoid necrosis, glomerular hyalinization, and infiltration of inflammatory cells was scored using a semi quantitative grading system ranging from 0 to 3: 0 = none; 1 = mild; 2 = moderate; 3 = severe inflammation
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Purpose:
Autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant genetic disorder of lymphocyte homeostasis with defective Fas-mediated apoptosis. Current therapies for ALPS primarily target autoimmune manifestations with non-specific immune suppressants with variable success thus highlighting the need for better therapeutics for this di...
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PurposeJacobsen syndrome (JS) is a rare form of genetic disorder that was recently classified as a syndromic immunodeficiency. Available detailed immunological data from JS patients are limited.Methods
Clinical and immunological presentation of twelve pediatric patients with JS by means of revision of clinical records, flow cytometry, real-time PCR...
Citations
... In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of IL-17 and IFN-γ production and proliferation of CD4 T cells, presumably Th1 and Th17. In an autoimmune lymphoproliferative (ALPS) mouse model, tofactinib treatment decreased expression of TCRαβ(+)CD4(-)CD8(-)T lymphocyte numbers while it increased CD8( +) T cells without a remarkable effect on CD4(+) lymphocytes including FoxP3(+) regulatory T cells 13 . ...
Tofactinib is a JAK inhibitor approved for ulcerative colitis in humans. Despite of its’ proven effectiveness in humans, mechanistic data are scarce on the effectiveness of Tofactinib in experimental colitis in mice. We induced experimental colitis by transfer of CD4+CD25− isolated T cells into RAG2−/− (T and B cell deficient) mice and treated these mice with tofacitinib for 5–6 weeks either with a dosage of 10 or 40 mg/kg body weight immediately after CD4+ transfer or started treatment after first symptoms of disease for several weeks. While treatment with tofacitinib immediately after transfer resulted in an enhanced expansion of CD4+ T cells and did not prevent occurrence of colitis, treatment after start of symptoms of colitis ameliorated disease activity on a clinical basis and in histological analyses. Tofacitinib is effective in the treatment of murine experimental T cell transfer colitis, however does not prevent occurrence of disease.
... In vitro experiments indicated that the effects of tofacitinib were mediated through suppression of IL-17 and IFN-γ production and proliferation of CD4 T cells, presumably Th1 and Th17. In an autoimmune lymphoproliferative (ALPS) mouse model, tofactinib treatment decreased expression of TCRαβ(+)CD4(-)CD8(-)T lymphocyte numbers while it increased CD8(+) T cells without a remarkable effect on CD4(+) lymphocytes including FoxP3(+) regulatory T cells 13 . ...
Introduction: Tofactinib is a JAK inhibitor approved for ulcerative colitis in humans. Despite of its’ proven effectiveness in humans, mechanistic data are scarce on the effectiveness of Tofactinib in experimental colitis in mice.
Methods: We induced experimental colitis by transfer of CD4 + CD25- isolated T cells into lymphopenic RAG2-/- mice and treated these mice with tofacitinib for 5–6 weeks either with a dosage of 10 or 40 mg/kg body weight immediately after CD4 + transfer or started treatment after first symptoms of disease for several weeks.
Results: While treatment with tofacitinib immediately after transfer resulted in an enhanced expansion of CD4 + T cells and did not prevent occurrence of colitis, treatment after start of symptoms of colitis ameliorated disease activity on a clinical basis and in histological analyses.
Discussion: Tofacitinib is effective in the treatment of murine experimental T cell transfer colitis, however does not prevent occurrence of disease.
... Tofacitinib is a non-selective JAK inhibitor, and is approved by the Food and Drug Administration (FDA) for RA and psoriasis [6,13]. Previous studies showed remarkable therapeutic efficacies of tofacitinib on mice models of certain autoimmune diseases such as SKG mice (an animal model of RA), interstitial lung disease in SKG mice, autoimmune lymphoproliferative syndrome (ALPS), and murine lupus [13][14][15][16][17]. ...
... Tofacitinib is the first generation jakinib that blocks multiple JAKs targeting a wide range of cytokines and has widespread immunosuppressive activity for T helper cells, antibody-producing B cells, antigen-presenting macrophages, DCs, and other mononuclear cells [14][15][16][17]. Tofacitinib is also an FDA-approved drug for RA and psoriasis; however, little is known about its effect on scleroderma [6,13]. ...
... Tofacitinib ameliorated arthritis in SKG mice by the inhibition of CD4 + T cell proliferation in vivo and in vitro [15]. In contrast, CD4 + T cells were not affected by tofacitinib treatment in murine lupus and ALPS [14,17]. In addition, in a mouse model of ALPS, tofacitinib reduced the proportion of TCR αβ + CD4 À CD8 À doublenegative T cells with a concomitant robust increase in CD8 + T cells [17]. ...
Background
Janus kinase (JAK)-signal transducer and activator of transcription (STAT) was hyperactivated in biopsies from patients with systemic sclerosis (SSc) and in several autoimmune disease models. Tofacitinib, a pan-JAK inhibitor, blocks the downstream signaling of multiple cytokines and has exhibited therapeutic efficacy in various autoimmune diseases, although its immunomodulating property in scleroderma is unclear.
Objective
To evaluate the effect of tofacitinib on the modulation of cytokine-producing T and B cells, and proinflammatory cells in a mouse model of SSc.
Methods
Bleomycin (BLM) -induced SSc was induced by intradermal injection of BLM or PBS for control. Mice received intraperitoneal tofacitinib (20 mg/kg) or vehicle 3 times per week from day 0 to 28. Mice were sacrificed at day 28 after the last BLM/PBS injection.
Results
Tofacitinib administration significantly alleviated fibrosis of the skin and lungs in scleroderma mouse model. Furthermore, tofacitinib suppressed adaptive and innate immune responses by reducing splenocytes, total lymphocytes, CD4⁺ T helper cells (especially Th2 and Th17 subtypes), IL-6-producing effector B cells, PDCA-1⁺ dendritic cells in the spleen, and infiltration of F4/80⁺, CD206⁺ and CD163⁺ macrophages in the skin and lungs. Conversely, tofacitinib increased the proportions of splenic regulatory T and B cells. The mRNA expression of extracellular matrix proteins and fibrogenic cytokines was downregulated by tofacitinib in both the skin and lungs.
Conclusion
These observations suggest JAK inhibition as a therapeutic approach for the treatment of inflammatory and fibrotic diseases, and highlight the potential of tofacitinib as a promising candidate for treating patients with scleroderma.
... Clinically, also effects on Tregs (i.e., frequency) were investigated and a potential association between Tregs and the clinical response was explored. However, the amount of data presented in published studies (i.e., on local and systemic Treg frequency and functionality in mice and men, but also in vitro) was much more extensive than present in the dossier reports, although for one of the JAK inhibitors only one literature study was available (151)(152)(153)(154)(155)(156)(157)(158). ...
Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.
... Treatment was initiated after two weeks of tumor growth and continued for four weeks at ~2/3 of the maximal tolerated dose of tofacitinib (21.5 mg/kg/day by subcutaneous infusion). 38 Encouragingly, we found significantly increased murine survival in this cell line model ( Figure Repurposing tofacitinib as anti-myeloma therapy haematologica | 2018; 103(7) Figure 6. Tofacitinib shows synergy with venetoclax only in the coculture setting. ...
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in co-culture with marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.
... In this study, we demonstrated significant decreases in anti-dsDNA antibodies, proteinuria, and splenomegaly in TOFA alone and TOFA + DEXA-administered SLEmouse group (Fig. 1) and amelioration of glomerular nephritis in TOFA + DEXA-treated SLE-prone mouse, BWF1 (Fig. 2). Previous report revealed that TOFA is immunologically effective for another SLE-prone mouse, MRL [20] with different genetic background from BWF1. TOFA + DEXA treatment was also clinically effective for MRL (Additional file 1: Figure S1). ...
Background
We previously reported that JAK–STAT-pathway mediated regulation of IFN-regulatory factor genes could play an important role in SLE pathogenesis. Here, we evaluated the efficacy of the JAK inhibitor tofacitinib (TOFA) for controlling IFN signalling via the JAK–STAT pathway and as a therapeutic for SLE. ResultsWe treated NZB/NZW F1 mice with TOFA and assessed alterations in their disease, pathological, and immunological conditions. Gene-expression results obtained from CD4+ T cells (SLE mice) and CD3+ T cells (human SLE patients) were measured by DNA microarray and qRT-PCR. TOFA treatment resulted in reduced levels of anti-dsDNA antibodies, decreased proteinuria, and amelioration of nephritis as compared with those observed in control animals. Moreover, we observed the rebalance in the populations of naïve CD4+ T cells and effector/memory cells in TOFA-treated mice; however, treatment with a combination of TOFA and dexamethasone (DEXA) elicited a stronger inhibitory effect toward the effector/memory cells than did TOFA or DEXA monotherapy. We also detected decreased expression of several IFN-signature genes Ifit3 and Isg15 in CD4+ from SLE-prone mice following TOFA and DEXA treatment, and IFIT3 in CD3+ T cells from human patients following immunosuppressant therapy including steroid, respectively. Conclusion
Modulation of type I IFN signalling via JAK–STAT inhibition may exert a beneficial effect in SLE patients, and our results suggest that TOFA could be utilised for the development of new SLE-specific therapeutic strategies.
... Mutations of JAK or STAT in humans are associated with severe immune/autoimmune dysfunction, revealing the fundamental role of this pathway in the induction and regulation of immune responses [129][130][131]. Notably, a series of JAK-STAT signaling cytokines, especially type I IFNs, TNF-α, IL-10, and IL-6 as well as the hormone prolactin have been implicated in the pathogenesis of SLE [132][133][134]. As previously mentioned, the biological actions of TNF-α are mediated by two cell surface receptors, TNFR-1 and TNFR-2. ...
Tumor necrosis factor-α (TNF-α) is a central regulator of inflammation, and TNF-α antagonists may be effective in treating inflammatory disorders in which TNF-α plays a major pathogenic role. TNF-α has also been associated with inflammatory mechanisms related to implantation, placentation, and pregnancy outcome. TNF-α is secreted by immune cells and works by binding to TNFR1 and TNFR2 cell receptors. TNF-α is also related to JAK/STAT pathways, which opens up hypothetical new targets for modifying. The accurate balance between Th1 cytokines, mainly TNF-α, Th17, and Th2, particularly IL-10 is essential to achieve good obstetric outcomes. TNF-α targeted therapy could be rational in treating women with obstetric complication related to overproduction of TNF-α, such as recurrent pregnancy loss, early and severe pre-eclampsia, and recurrent implantation failure syndrome, all “idiopathic” or related to aPL positivity. Along the same lines, Th1 cytokines, mainly TNF- α, play a leading pathogenic role in rheumatic and systemic autoimmune diseases occurring in women and, to a lesser extent, in men of reproductive age. These disorders have to be clinically silent before pregnancy can be recommended, which is usually only possible to achieve after intensive anti-inflammatory and immunosuppressive treatment, TNF-α blockers included. Physicians should be aware of the theoretic potential but low embryo-fetal toxicity risk of these drugs during pregnancy. From an updated review in May 2016, we can conclude that TNF-α blockers are useful in certain “refractory” cases of inflammatory disorders related to poor obstetric outcomes and infertility. Furthermore, TNF-α blockers can be safely used during the implantation period and pregnancy. Breastfeeding is also permitted with all TNF-α inhibitors. Since data on the actual mechanism of action of JAK-STAT in inflammatory obstetric disorders including embryo implantation are scarce, for the time being, therapeutic interventions in this setting should be discouraged. Finally, adverse effects on sperm quality, or causing embryo-fetal anomalies, in men treated with TNF inhibitors have not been described.
... ALPS is general caused by the defects in Fas signalling and is manifested by chronic non-malignant lymphoproliferation and autoimmunity with massive accumulation of lymphocytes, resulting in splenomegaly and lymphadenopathy [13,19,20]. The hallmark feature of the disease is an expanded homogenous population of T cell that is TCRab+CD4ÀCD8À double-negative T (DNT) cell in peripheral blood and lymphoid organs [21,22]. Previous research has shown that the genetical manipulated TCF1 gene and generated mutant mice have shown that TCF1 has an essential role during preT cell receptor (TCR) and TCR-dependent stages of T cell development, and regulates various aspects of T cell development and CD4 and CD8 T cell function, such as the differentiation of mature CD4 T cells into T helper lineages [5]. ...
Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease, which is characterized by non-malignant autoimmune lymphoproliferation. TCF1 is a key effector in the canonical Wnt/?-catenin pathway, regulating the development, activation and function of T cells. In this study, we aimed to explore the potential role of TCF1 in the development of ALPS-like phenotypes of lpr/lpr mice. We acquired TCF1(-/-) lpr/lpr double mutant mice by crossing TCF1 deficiency mice with lpr/lpr mice. Splenocyte compositions, serum cytokines levels, anti-dsDNA antibody production and kidney pathology were examined in the TCF1(-/-) lpr/lpr mice. With these examinations, we revealed that TCF1 deficiency relieved most manifestations of ALPS-like phenotype which were caused by Fas mutation in TCF1(-/-) lpr/lpr mice. Splenocyte total numbers and compositions were down-regulated to the similar levels with wildtype mice. TE and TEM cells were decreased in TCF1(-/-) lpr/lpr compared with lpr/lpr mice. The levels of autoantibodies and proinflammatory factors in serum, and the histopathology changes and the relative mRNA levels of proinflammatory factors in kidney all displayed parallel tendency in TCF1(-/-) lpr/lpr mice. Our study demonstrated that TCF1 deficiency ameliorated the ALPS-like phenotypes of TCF1(-/-) lpr/lpr mice, which might indicate a potential therapeutic direction for ALPS. This article is protected by copyright. All rights reserved.
... In some cases, insufficient effectiveness of antitumor remedies can be explained by specific vital functions in the transformed cellular elements and pronounced differences in the development of various tumor types [1][2][3][4][5]. The recent studies on molecular biology and genetics of tumor cells revealed novel and highly specific molecular targets for chemotherapy [2,7,[10][11][12][13]. These fundamental findings made it possible to develop a number of original targeted drugs to treat some tumors that are resistant to the action of routine cytostatics. ...
... Modern pharmacology hopes to solve a number of tasks in antitumor therapy by investigation of intracellular signaling in the transformed cells [2,13,15]. At present, it advanced and effectively employed the drugs targeted on individual signal molecules implemented in realization of vital functions of various tumor cells (cyclin-dependent kinases, protein kinases, etc.) including the suppressors of JAK family tyrosine kinases [2,7,[10][11][12]. ...
... For instance, while JAK3 is a specific kinase in some limited number of cells types of adult organism (certain cells of immune system, hematopoietic progenitors, etc.) [9], it also plays an important role in determining the proliferation and differentiation potential of the tumor cells of various origin. Taking into consideration the potentially wide spectrum of the side effects and complications of chemotherapy, the selective inhibition of JAK3 in treatment of malignant tumors seems to be safer than the use of pan-JAK inhibitors [10,13]. ...
Mice with Lewis lung carcinoma were used to study the antitumor and antimetastatic effects of JAK3 inhibitor. The study revealed no effect of JAK3 inhibitor on the growth of primary tumor node, but found a pronounced inhibition of hematogenous spread of the pathologic process into the lungs. In vitro blockade of JAK3 in cultured Lewis lung carcinoma produced no effect on the count of the stem tumor cells and stimulated functions of committed elements. In addition, blockade of JAK3 significantly elevated maturation index of the tumor tissue.
... Spleens from the tofacitinib-treated mice were reduced in size and total cell number when compared to vehicle-treated mice (Figure 2A left panel and Supplemental Figure 3A). Moreover, total numbers of T cells, (Figure 2A right panel) CD8 + T cells and DN T cells were significantly reduced, whereas CD4 + T cells were not ( Figure 2B) (29). In contrast, CD4 + T cells, total B cells, CD138 + B cells. ...
Objectives:
Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. To date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a Janus kinase (JAK) inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized.
Methods:
MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice.
Results:
Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated NETs formation and significantly increased endothelium-dependent vasorelaxation and endothelial differentiation. The drug was effective as both preventive and therapeutic strategies.
Conclusions:
Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage. This article is protected by copyright. All rights reserved.
