FIGURE 5 - uploaded by Carlos E Tadokoro
Content may be subject to copyright.
Blockage of CTLA-4 leads to increased resistance to T. cruzi (Y strain) infection in mice. C57BL/6 mice (10/group) were treated with 100 g of control hamster IgG (f) or hamster anti-CTLA-4 (OE) mAb, and 4 h later infected with 10 3 T. cruzi trypomastigote forms (Y strain, A). Alternatively, mice (five per group) were infected with 10 4 parasite forms and 24 h later treated with the anti-CTLA-4 Ab (B and C). Parasitemia (A and B) and survival rates (C) were evaluated at different time points. Asterisks indicate statistical significance, p 0.05 () or p 0.001 () (MannWhitney U test) compared with the values obtained from control IgG-treated mice at the same time point. Similar results were obtained in three (A) or two (B and C) other experiments performed independently.
Source publication
Recent studies have revealed an important role for CTLA-4 as a negative regulator of T cell activation. In the present study, we evaluated the importance of CTLA-4 to the immune response against the intracellular protozoan, Trypanosoma cruzi, the causative agent of Chagas' disease. We observed that the expression of CTLA-4 in spleen cells from naiv...
Contexts in source publication
Context 1
... numbers of T. cruzi. Parasitemia and mortality were evaluated at different time points after the infection. When infection was performed with 10 3 parasite forms, the treatment with anti-CTLA-4, but not with control hamster IgG, led to a significant reduction in parasitemia, most nota- bly at days 9 ( p 0.01) and 10 ( p 0.05) postinfection (Fig. 5A). Since 100% of the C57BL/6 mice infected with 10 3 forms sur- vive acute and chronic phases of infection (6, 10), we next infected C57BL/6 mice with 10 4 forms (which leads to death from acute disease in all mice infected) and 24 h later treated them with anti- CTLA-4 or control IgG. This treatment schedule has been used before to ...
Context 2
... (which leads to death from acute disease in all mice infected) and 24 h later treated them with anti- CTLA-4 or control IgG. This treatment schedule has been used before to efficiently block CTLA-4 in mice infected with other intracellular parasites (31), and it was preferred instead of the treat- ment schedule used in the previous experiment (Fig. 5A) in an attempt to maximize the efficacy of CTLA-4 blockage. We hy- pothesized that infection with either higher inoculums or more virulent strains could result in different kinetics of T cell activation and consequently of CTLA-4 expression, which would be presum- ably more efficiently blocked if the neutralizing Ab anti-CTLA-4 was ...
Context 3
... expression induced by the infection in vivo is delayed compared to that observed in vitro, we assumed that the anti-CTLA-4 Ab effects would last longer if administrated 24 h after infection instead of 4 h before the infection. Indeed, the treat- ment with anti-CTLA-4 24 h after the infection resulted in a sig- nificant decrease in parasitemia (Fig. 5B). Nine days after infec- tion, anti-CTLA-4-treated mice had a 6-fold decrease in the number of parasites in the blood as compared with the IgG-treated group. At day 10 after infection, parasitemia was still significantly smaller in the anti-CTLA-4-treated group (3-fold lower) in com- parison to the parasitemia of the IgG-treated group. ...
Context 4
... com- parison to the parasitemia of the IgG-treated group. By day 11 postinfection, the differences between the two groups were no longer statistically significant. Evaluation of mortality rates showed that while 100% of the IgG-treated mice died by day 20 after infection, all of the anti-CTLA-4-and T. cruzi-infected mice survived the acute phase (Fig. 5C). A significant reduction in par- asitemia levels and similar rescue of mortality were observed when mice were treated with anti-CTLA-4 Ab 4 h before instead of 24 h after the infection with 10 4 parasite forms (data not ...
Similar publications
The ephemeral placenta provides a noncontroversial source of young, healthy cells of both maternal and fetal origin from which cell therapy products can be manufactured. The 2 advantages of using live cells as therapeutic entities are: (a) in their environmental-responsive, multifactorial secretion profile and (b) in their activity as a “slow-relea...
Microalgae as feedstock for biofuel production have attracted serious consideration as an important sustainable source of energy. For biodiesel production with microalgae, a series of consecutive processes should be performed as selection of adequate microalgal strains, mass culture, cell harvesting, oil extraction and transesterification. The aim...
Objective: Gouty arthritis is an intense inflammatory arthritis induced by monosodium urate (MSU) crystals. Macrophages play critical roles in the development of gout. Previous studies suggest that the transforming growth factor-β (TGF-β) signaling can regulate the inflammation through direct effects on macrophage function through TGF-β inducible e...
To evaluate the use of high-dose sequential chemotherapy in a Brazilian population.
High-dose cyclophosphamide followed by autologous hematopoietic stem cell transplantation is an effective and feasible therapy for refractory/relapsed lymphomas; this regimen has never before been evaluated in a Brazilian population. All patients (106 with high-grad...
The number of viable precursor cells actually reinfused into patients after high-dose chemotherapy is one of the most clinically important variables determining graft success or failure. A modified, previously described flow cytometric method based on annexin V staining was therefore applied to assess the degree of apoptosis and necrosis in cryopre...
Citations
... The Allami [17] study was the first to investigate the influence of CTLA-4 +49A/G polymorphism on the susceptibility to toxoplasmosis in Iraq and found that the AG genotype and G allele protect against the disease. There have been several studies showing the influence of intracellular parasites on the expression of CTLA-4, such as those by Martins et al., [18] who found a substantial increase in CTLA-4 expression in infected spleen cells from noninfected mice compared to those from infected animals. The mechanisms bearing the increased and sustained CTLA-4 expression of T-cells induced by Toxoplasma infection are not fully understood. ...
... It could also result from the presence of soluble factors secreted by the infected cells, such as cytokines. [18] When the distribution of CTLA-4 levels was compared according to the type of Toxoplasma antibodies in different study groups, a high level of CTLA-4 was seen in the aborted women group with all types of anti-Toxoplasma antibodies. As well as, the highest levels were obtained in the aborted women group with IgG-positive antibodies (43.47%) than in the other toxoplasmosis groups with different antibody types. ...
... [11] As combinatorial approaches of CTLA-4 blockade with other therapeutic agents, such as radiation and chemotherapy, have proven to be effective in the regression of tumors in various malignancy murine models, a wide range of cancers, including melanoma, small cell lung cancer, nonsmall cell lung cancer, and prostate cancer, are now being studied using these approaches. [18] Moreover, there is a highly significant increase in this parameter 766.4 ± 300.2 in the aborted group, as compared with its levels in other infected and control groups when comparing study groups. In fact, this is the first study that measures CTLA-4 serum levels in women with different toxoplasmosis types and comparison that level with each other and with control groups. ...
... Studies have shown that many pathogens (including parasites, bacteria, and viruses) can use the PD-1 pathway to evade host adaptive immunity (11)(12)(13)(14). During Trypanosoma cruzi infection, blockade of CTLA-4 resulted in increased host resistance to T. cruzi infection, which was associated with increased production of IFN-g, TNF-a, and NO (15). Butler NS et al. reported that therapeutic blockade of LAG-3 and PD-L1 rapidly cleared blood-stage Plasmodium vivax in mice (16). ...
Haemonchus contortus is an important parasitic nematode of ruminants. Previous studies showed that H. contortus escape the immunity through complex mechanisms, including releasing excretory/secretory proteins (ESPs) to modulate the host immune response. However, the detailed mechanism through which H. contortus excretory/secretory proteins (HcESPs) promote immune evasion remains unknown. In the present study, we demonstrated that HcESPs inhibit the adaptive immune response of goats including downregulation of immune cell antigen presentation, upregulation of immune checkpoint molecules, activation of the STAT3/PD-L1 pathway, and activation of immunosuppressive regulatory T (Treg) cells. Furthermore, HcESPs reversed the LPS-induced upregulation of pro-inflammatory mediators in PBMCs by inhibiting the TLR4/NF-κB/MAPKs/NLRP3 signaling pathway. Our study provides a better understanding of the evasion mechanisms for H. contortus, which could be helpful in providing an alternative way to prevent the infection of this parasite.
... The binding of an immune checkpoint molecule to its cognate ligand on another cell effectively suppresses the immune cell activity by signaling through an inhibitory pathway. This immune cell downregulation helps to prevent autoimmunity, graft rejection and overactive inflammatory responses, by damping the activation signal [2][3][4][5][6]. Many cancer cells exploit this phenomenon by upregulating immune checkpoint ligands on their surface, such that when an immune checkpoint molecule binds to its cognate ligand on a cancer cell, the immune cell is 'turned off', thereby allowing the cancer cells to proliferate without inhibition by an immune response. ...
Immune checkpoint blockade (ICB) comprising monoclonal antibodies (mAbs) against immune ‘checkpoints’, such as CTLA-4 and the PD1/PDL1 axis have dramatically improved clinical outcomes for patients with cancer. However, ICB by itself has failed to provide benefit in a wide range of solid tumors, where recurrence still occurs with high incidence. These poor response rates may be due to the therapeutic shortcomings of ICB; namely, a lack of cancer-specific cytotoxicity and ability to debulk tumors. To overcome these limitations, effective ICB therapy may require the combination with other complementary therapeutic platforms. Here, we propose that photothermal therapy (PTT) is an ideal therapeutic modality for combination with ICB because it can generate both tumor-specific cytotoxicity and immunogenicity. PTT elicits these specific effects because it is a localized thermal ablation technique that utilizes light-responsive nanoparticles activated by a wavelength-matched laser. While ICB immunotherapy alone improves cancer immunogenicity but does not generate robust antitumor cytotoxicity, nanoparticle-based PTT elicits targeted and controlled cytotoxicity but sub-optimal long-term immunogenicity. Thus, the two platforms offer complementary and potentially synergistic antitumor effects, which will be detailed in this review. We highlight three classes of nanoparticles used as agents of PTT (i.e., metallic inorganic nanoparticles, carbon-based nanoparticles and organic dyes), and illustrate the potential for nanoparticle-based PTT to potentiate the effects of ICB in preclinical models. Through this discussion, we aim to present PTT combined with ICB as a potent synergistic combination treatment for diverse cancer types currently refractory to ICB as well as PTT monotherapies.
... Two hypotheses are given as to why this may have happened. First, the virulent parasites induce an internal mechanism to suppress immunomodulation, as reported in the CTLA-4 blockage by Trypanosoma cruzi (Martins et al., 2004) and the excessive levels of resultant cytokines were lethal. Second, since the severely ill mice had higher expression levels of IFNγ than surviving mice and we demonstrated that its balanced production is important to overcome disease, then the virulent parasite could be stimulating its pathway. ...
In most of the world Toxoplasma gondii is comprised of archetypal types (types I, II and III); however, South America displays several non-archetypal strains. This study used an experimental mouse model to characterize the immune response and parasite kinetics following infection with different parasite genotypes. An oral inoculation of 50 oocysts per mouse from T. gondii M4 type II (archetypal, avirulent), BrI or BrIII (non-archetypal, virulent and intermediate virulent, respectively) for groups (G)2, G3 and G4, respectively was used. The levels of mRNA expression of cytokines, immune compounds, cell surface markers and receptor adapters [interferon gamma (IFNγ), interleukin (IL)-12, CD8, CD4, CD25, CXCR3 and MyD88] were quantified by SYBR green reverse transcription-quantitative polymerase chain reaction. Lesions were characterized by histology and detection by immunohistochemistry established distribution of parasites. Infection in G2 mice was mild and characterized by an early MyD88-dependent pathway. In G3, there were high levels of expression of pro-inflammatory cytokines IFNγ and IL-12 in the mice showing severe clinical symptoms at 8–11 days post infection (dpi), combined with the upregulation of CD25, abundant tachyzoites and tissue lesions in livers, lungs and intestines. Significant longer expression of IFNγ and IL-12 genes, with other Th1-balanced immune responses, such as increased levels of CXCR3 and MyD88 in G4, resulted in survival of mice and chronic toxoplasmosis, with the occurrence of tissue cysts in brain and lungs, at 14 and 21 dpi. Different immune responses and kinetics of gene expression appear to be elicited by the different strains and non-archetypal parasites demonstrated higher virulence.
... Once T cells are activated by CD28-CD80/CD86 signal, they enhance expression of cytotoxic T lymphocyte antigen-4 (CTLA-4, also named CD152), which is another receptor for CD80/ CD86. CTLA-4 is shown to be involved in maintenance of peripheral tolerance; inhibition of immune response against tumors and infectious diseases; as well as increased severity of autoimmune diseases (Gregor et al., 2004;Martins et al., 2004). ...
Malaria is a life-threatening infectious disease, affecting over 250 million individuals worldwide each year, eradicating malaria has been one of the greatest challenges to public health for a century. Growing resistance to anti-parasitic therapies and lack of effective vaccines are major contributing factors in controlling this disease. However, the incomplete understanding of parasite interactions with host anti-malaria immunity hinders vaccine development efforts to date. Recent studies have been unveiling the complexity of immune responses and regulators against Plasmodium infection. Here, we summarize our current understanding of host immune responses against Plasmodium-derived components infection and mainly focus on the various regulatory mechanisms mediated by recent identified immune regulators orchestrating anti-malaria immunity.
... However, these molecules are also associated with T cell exhaustion during chronic infections (24). Acute experimental models of ChD have shown that the infection induces the transient expression of inhibitory receptors, such as PD-1 (CD279) and CTLA-4 (CD152), on T cells and tissueinfiltrating T cells in the myocardium (91,92). In addition, acute T. cruzi-infected mice treated with blocking antibodies against PD-1 or PD-L1 show reduced parasitemia and parasitism and an increased cardiac inflammatory response and mortality compared to infected mice treated with an isotype control (IgG) (91). ...
... In addition, acute T. cruzi-infected mice treated with blocking antibodies against PD-1 or PD-L1 show reduced parasitemia and parasitism and an increased cardiac inflammatory response and mortality compared to infected mice treated with an isotype control (IgG) (91). In contrast, acute T. cruzi-infected mice treated with anti-CTLA-4 show reduced parasitemia and mortality compared to mice treated with an isotype control (IgG) (92). In chronic experimental models of ChD and in patients with a severe form of chronic ChD, a continuous increase in inhibitory receptor expression and co-expression on T cells from peripheral blood and cells from cardiac tissue has been observed (68,93). ...
Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi, represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20–40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi-infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi-infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi-infected mice. Acute ChD induced a high antigen-specific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes the dysfunctionality of T cells, and these changes might correlate with ChD progression. Thus, these results constitute a model that will facilitate an in-depth search for immune markers and correlates of protection, as well as long-term studies of new immunotherapy strategies for ChD.
... Checkpoint blockade can reestablish the immune response by blocking key inhibitory interactions and led to parasite and virus burden decrease in different infectious disease models (16,17). During acute T. cruzi infection, both anti-CTLA-4 and anti-PD1 and/or anti-PDL1 monoclonal antibody treatment can improve cellular immune responses and decrease heart parasite load (18,19). Furthermore, rescue of T cells may need costimulatory signaling through CD28 to improve recovery of immune response in treatment with PD1-PDL1-blocking antibodies (20). ...
Chagas disease is a neglected parasitic infection that affects around six to seven million people, mainly in Latin America. About 30–35% of infected people present chronic Chagas cardiomyopathy (CCC), which eventually leads to death. This condition is characterized by local parasite persistence and leukocyte infiltration. In a murine model of CCC, we observed that among infiltrating leukocytes, CD4⁺ and CD8⁺ T cells were in higher frequency in the heart of chronically infected mice, although elevated expression of the regulatory molecules programmed cell death protein 1 (PD1) and PDL1 suggested these cells could be inhibited. To investigate if PD1–PDL1 interaction in the heart of chronically infected mice negatively impacts on the local immune response, facilitating parasite persistence, and progression to CCC, we attempted to recover the local immune response by treating chronically infected mice with anti-PD1 and anti-PDL1-blocking antibodies together with irradiated Trypanosoma cruzi, which provides immune response boosting. Irradiated parasites promote expression of costimulatory molecules in dendritic cells and provide specific parasite antigen, which should aid T cell reactivation upon checkpoint blockade. Following treatment, there was an increased frequency of heart-infiltrating CD4⁺ and CD8⁺ T cells with an effector memory phenotype, an increased histopathology score and decreased heart rate, supporting our previous hypothesis of local immunosuppression induced by this pathway during CCC. In addition, blood parasitemia was reduced, which was associated with increased T. cruzi-specific immunoglobulin G 1 antibodies. However, no difference was observed in cytokine production or T. cruzi burden in the hearts of treated mice. Taken together, our results suggest PD1–PDL1 interaction protects the heart from excessive immune response.
... Corroborating with our results, Souza et al. showed a higher frequency of this inhibitory molecule in IND but not in CARD patients (35). CTLA-4 also implicated in the modulation of the immune response against T. cruzi by affecting the mechanisms that control IFN-γ and nitric oxide production during the acute phase of Chagas disease (45). We propose that the interaction of CD86 with CTLA-4 in asymptomatic patients may be a mechanism of immunoregulation to prevent tissue damage and the pathology progression. ...
In the chronic phase of Chagas disease, 60% of the patients develop the asymptomatic form known as indeterminate (IND). The remaining 30% of the patients develop a life-threatening form in which digestive and/or cardiac (CARD) alterations take place. The mechanisms underlying the development of severe forms of Chagas disease remain poorly understood. It is well known that interactions between immune cells such as monocytes and lymphocytes drive immune responses. Further, the co-stimulatory molecules CD80 and CD86 expressed by monocytes and subsets induce lymphocyte activation, thereby triggering cellular immune response. Here, we revealed, for the first time, the functional-phenotypic profile of monocytes subsets in Chagas disease. Using flow cytometry, we evaluated the effect of in vitro stimulation with Trypanosoma cruzi antigens on the expression of the co-stimulatory molecules CD80 and CD86 in different monocyte subsets of patients with IND and CARD clinical forms of Chagas disease. We also assessed the expression of toll-like receptor (TLR)-2, TLR-4, TLR-9, HLA-DR, IL-10, and IL-12 in the monocyte subsets and of CTLA-4 and CD28, ligands of CD80 and CD86, in T lymphocytes. CD86 expression in all monocyte subsets was higher in IND patients when compared with non-infected (NI) individuals. After stimulation with T. cruzi, these patients also showed a higher frequency of CD4⁺CTLA-4⁺ T lymphocytes than NI individuals. We found an association between CD80 and CD28, and between CD86 and CTLA-4 expression, with a high frequency of regulatory T (Treg) cells in IND patients. We proposed that CD86 may be involved in immunoregulation by its association with CTLA-4 in asymptomatic patients. CD86 and CTLA-4 interaction may influence Treg activation, and this could represent a new strategy to control inflammation and tissue damage.
... Immunotherapy (IT) with CTLA-4 blockade has mostly been conducted against tumoral cells; nonetheless, recent evidence has shown that CTLA-4 expression is associated with reduced secretion of TNF-α and IFN-γ and enhanced frequency of memory CD8 + lymphocytes in experimental L. monocytogenes infection (27). Similarly, CTLA-4 blockade induced higher production of IFN-γ and NO when T cells were stimulated with Trypanosoma cruzi antigens, although it did not restore lymphocyte proliferation (28). Furthermore, despite few clinical trials concerning CTLA-4 blockade to control infectious diseases, HCV patients demonstrated promising results after this therapy (29). ...
Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.
... For example, during infection with a more virulent P. yoelii variant, CTLA-4 blockade induced markedly increased serum levels of TNF-α accompanied by severe inflammation and reduced survival 47 . During Trypanosoma cruzi infection, CTLA-4 blockade resulted in increased NO production in vivo and in vitro, and increased resistance to infection with the Y and Colombian strains of T. cruzi, and also led to increased survival rate 48 . The reality of the phenomenon is now demonstrated in E. multilocularis infection; however, detailed mechanisms associated with LAG3 and 2B4 expression, and other markers of T cell exhaustion, Figure 8. ...
The local immune mechanisms responsible for either self-healing or sustained chronic infection are not clear, in the development of E. multilocularis larvae. Here, we developed a suitable experimental model that mimics naturally infected livers, according to the parasite load. We demonstrated that local cellular immunity and fibrogenesis are actually protective and fully able to limit metacestode growth in the liver of low or medium dose-infected mice (LDG or MDG), or even to clear it, while impairment of cellular immunity is followed by a more rapid and severe course of the disease in high dose-infected mice (HDG). And recruitment and/ or proliferation of memory T cells (including CD4 Tem, CD8 Tcm and CD8 Tem) and imbalance of T1/T2/T17/Treg-type T cells in liver were not only associated with clearance of the parasite infection in LDG, but also with increased hepatic injury in HDG; in particular the dual role of CD8 T cells depending on the parasite load and the various stages of metacestode growth. Besides, we first demonstrate the association between LAG3- or 2B4-expressing T cells exhaustion and HD inocula in late stages. Our quantitative experimental model appears fully appropriate to study immunomodulation as a therapeutic strategy for patients with Alveolar Echinococcosis.
