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CTLA-4
Terms modified by CTLA-4 Selected AbstractsPhenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetesDIABETIC MEDICINE, Issue 10 2006Y. Tsutsumi Abstract Aims To investigate the contribution of regulatory T cells and co-stimulatory molecules in CD4+ T cells to the development of Type 1 diabetes (T1D). Methods Twelve patients with T1D, nine patients with systemic lupus erythematosus (SLE), and 12 age-matched healthy control subjects participated. We analysed the proportions of CD25+CD4+ T cells and natural killer T cells (NKT cells), and the expression levels of Foxp3, CTLA-4, CD28, ICOS, PD-1 and BTLA in peripheral blood mononuclear cells and purified CD4+ T cells. Results There were no significant differences in the proportions of CD25+ CD4+ T cells or NKT cells among the three groups. PD-1 expression levels of peripheral CD4+ T cells from T1D patients were significantly lower than those from healthy control subjects (P = 0.00066). In contrast, PD-1 expression levels were similar in SLE patients and healthy control subjects. The expression levels of Foxp3, CTLA-4, CD28, ICOS and BTLA were similar in the three groups. Conclusions Decreased expression of the PD-1 gene in CD4+ T cells may contribute to the development and/or maintenance of autoimmune T1D. As the population studied was small and heterogeneous, further studies are required to confirm the findings. [source] Acquisition of regulatory function by human CD8+ T cells treated with anti-CD3 antibody requires TNFEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Vitaly Ablamunits Abstract Anti-CD3 mAb can modulate graft rejection and attenuate autoimmune diseases but their mechanism(s) of action remain unclear. CD8+ T cells with regulatory function are induced in vitro by Teplizumab, a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells. They inhibit CD4+ T-cell proliferation by mechanisms involving TNF and CCL4, and by blocking target cell entry into G2/M phase of cell cycle but neither kill them, nor compete for IL-2. CD8+ Treg can be isolated from peripheral blood following treatment of patients with Type 1 diabetes with Teplizumab, but not from untreated patients. The induction of CD8+ Treg by anti-CD3 mAb requires TNF and signaling through the NF-,B cascade. The CD8+ Treg express CD25, glucocorticoid-induced TNF receptor family, CTLA-4, Foxp3, and TNFR2, and the combined expression of TNFR2 and CD25 identifies a potent subpopulation of CD8+ Treg. These studies have identified a novel mechanism of immune regulation by anti-CD3 mAb and markers that may be used to track inducible CD8+ Treg in settings such as chronic inflammation or immune therapy. [source] HIV-1 impairs in vitro priming of naïve T cells and gives rise to contact-dependent suppressor T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 8 2010Karlhans F. Che Abstract Priming of T cells in lymphoid tissues of HIV-infected individuals occurs in the presence of HIV-1. DC in this milieu activate T cells and disseminate HIV-1 to newly activated T cells, the outcome of which may have serious implications in the development of optimal antiviral responses. We investigated the effects of HIV-1 on DC,naïve T-cell interactions using an allogeneic in vitro system. Our data demonstrate a dramatic decrease in the primary expansion of naïve T cells when cultured with HIV-1-exposed DC. CD4+ and CD8+ T cells showed enhanced expression of PD-1 and TRAIL, whereas CTLA-4 expression was observed on CD4+ T cells. It is worth noting that T cells primed in the presence of HIV-1 suppressed priming of other naïve T cells in a contact-dependent manner. We identified PD-1, CTLA-4, and TRAIL pathways as responsible for this suppresion, as blocking these negative molecules restored T-cell proliferation to a higher degree. In conclusion, the presence of HIV-1 during DC priming produced cells with inhibitory effects on T-cell activation and proliferation, i.e. suppressor T cells, a mechanism that could contribute to the enhancement of HIV-1 pathogenesis. [source] Abnormal CTLA-4 function in T cells from patients with systemic lupus erythematosusEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010Elizabeth C. Jury Abstract CTLA-4 is a critical gatekeeper of T-cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA-4 in SLE. Our results reveal increased CTLA-4 expression in FOXP3, responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA-4 was unable to regulate T-cell proliferation, lipid microdomain formation and phosphorylation of TCR-, following CD3/CD28 co-stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co-stimulation, there was no parallel increase in CTLA-4 expression, which would normally provide a break on T-cell proliferation. These defects were associated with exclusion of CTLA-4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA-4 dysfunction as a potential cause for abnormal T-cell activation in patients with SLE, which could be targeted for therapy. [source] Multiple functions of human T cells generated by experimental malaria challengeEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Stephen M. Todryk Abstract Protective immunity generated following malaria infection may be comprised of Ab or T cells against malaria Ag of different stages; however, the short-lived immunity that is observed suggests deficiency in immune memory or regulatory activity. In this study, cellular immune responses were investigated in individuals receiving Plasmodium falciparum sporozoite challenge by the natural (mosquito bite) route as part of a malaria vaccine efficacy trial. Parasitemia, monitored by blood film microscopy and PCR, was subsequently cleared with drugs. All individuals demonstrated stable IFN-,, IL-2 and IL-4 ex vivo ELISPOT effector responses against P. falciparum -infected RBC (iRBC) Ag, 28 and 90,days after challenge. However, infected RBC-specific central memory responses, as measured by IFN-, cultured ELISPOT, were low and unstable over time, despite CD4+ T cells being highly proliferative by CFSE dilution, and showed an inverse relationship to parasite density. In support of the observation of poor memory, co-culture experiments showed reduced responses to common recall Ag, indicating malaria-specific regulatory activity. This activity could not be accounted for by the expression of IL-10, TGF-,, FOXP3 or CTLA-4, but proliferating T cells expressed high levels of CD95, indicating a pro-apoptotic phenotype. Lastly, there was an inverse relationship between FOXP3 expression, when measured 10 days after challenge, and ex vivo IFN-, measured more than 100 days later. This study shows that malaria infection elicits specific Th1 and Th2 effector cells, but concomitant weak central memory and regulatory activity, which may help to explain the short-lived immunity observed. [source] CTLA-4 co-receptor impacts on the function of Treg and CD8+ T-cell subsetsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2009Christopher E. Rudd Abstract CTLA-4 has potent regulatory effects on the threshold of T-cell signalling and, in the process, guards against the development of hyper-proliferation and autoimmunity. Despite this, the role of CTLA-4 on specific T-cell subsets has been unclear. Such studies could shed light on both the function of CTLA-4, and on the contribution of the subsets to the disease phenotype of the Ctla4,/, mouse. Recently, a role for this co-receptor in the function of Treg has been outlined and, in this issue of the European Journal of Immunology, the selective targeting of the T-box transcription factor Eomes by CTLA-4 in the regulation of CD8+ cytolytic T-cell (CTL) effector function is shown. Together, these papers shed light on the role of CTLA-4 in different T-cell subsets. [source] ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007Josef Bodor Dr. Abstract Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25+CD4+ regulatory T cell (TR) assays mainly in activated Foxp3, effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25,CD4+ T cells antagonizes TR -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25, T cells induces constitutive expression of ICER/CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/CREM both in Foxp3 transductants as well as CD25, responder T cells suggesting that induction of TR function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25, responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligand-bearing Foxp3, effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in TR cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/CREM expression in activated CD25+ Foxp3, T cell effectors thus preventing them from producing IL-2. [source] Breakpoints in immunoregulation required for Th1 cells to induce diabetesEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2006Margaret Neighbors Abstract We describe a novel TCR-transgenic mouse line, TCR7, where MHC class,II-restricted, CD4+ T cells are specific for the subdominant H-2b epitope (HEL74,88) of hen egg lysozyme (HEL), and displayed an increased frequency in the thymus and in peripheral lymphoid compartments over that seen in non-transgenic littermate controls. CD4+ T cells responded vigorously to HEL or HEL74,88 epitope presented on APC and could develop into Th1 or Th2 cells under appropriate conditions. Adoptive transfer of TCR7 Ly5.1 T cells into Ly5.2 rat insulin promoter (RIP)-HEL transgenic recipient hosts did not lead to expansion of these cells or result in islet infiltration, although these TCR7 cells could expand upon transfer into mice expressing high levels of HEL in the serum. Islet cell infiltration only occurred when the TCR7 cells had been polarized to either a Th1 or Th2 phenotype prior to transfer, which led to insulitis. Progression from insulitis to autoimmune diabetes only occurred in these recipients when Th1 but not Th2 TCR7 cells were transferred and CTLA-4 signaling was simultaneously blocked. These findings show that regulatory pathways such as CTLA-4 can hold in check already differentiated autoreactive effector Th1 cells, to inhibit the transition from tolerance to autoimmune diabetes. See accompanying commentary at http://dx.doi.org/10.1002/eji.200636591 [source] In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2005Shigekazu Takahashi Abstract Cytotoxic T,lymphocyte antigen-4 (CTLA-4) induces major inhibitory signals for T,cell activation. From analyses of TCR-transgenic (Tg) CTLA-4-deficient mice, it has been believed that CTLA-4 does not affect thymocyte development. To focus upon the in vivo function of CTLA-4 in thymocyte development from a different aspect, we have established Tg mice expressing either full-length CTLA-4 (FL-Tg) or a mutant CTLA-4 lacking the cytoplasmic region (truncated, TR-Tg), and analyzed thymocyte development. TR-T,cells express much higher CTLA-4 on the cell surface than FL-T,cells, in which most CTLA-4 was localized in intracellular vesicles. While CTLA-4,/, mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA-4,/, background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double-positive thymocytes by injection of anti-CD3 Ab as well as the elimination of minor lymphocyte-stimulating antigen-reactive thymocytes were impaired in FL-Tg mice but not in TR-Tg mice. Functionally, cross-linking of CTLA-4 on thymocytes from FL-Tg mice, but not from TR-Tg mice, inhibited proliferation. These results reveal a potential role of CTLA-4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease. [source] Suppressive properties of human CD4+CD25+ regulatory T,cells are dependent on CTLA-4 expressionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2004Brigitte Birebent Abstract It has been demonstrated that T,cells with regulatory properties are present within the peripheral blood CD4+CD25+ T,cell compartment. Here, we describe an original method to purify human CD4+CD25+CD152+ T,lymphocytes as living cells by forcing the exportation of CTLA-4 molecules stored in intracellular vesicules at the cell surface. By doing so, we demonstrate that CD4+CD25+ T,cells contain a smaller and more homogeneous population enriched in cells with in vitro regulatory activity. Moreover, we show that this enrichment in regulatory T,cells is associated with an increased expression of Foxp3 and that CD4+CD25+CD152+ T,lymphocytes display a much stronger suppressive activity in controlling in vitro proliferation of alloantigen-specific T,cells than CD4+CD25+CD152, T,lymphocytes purified in parallel. Lastly, by purifying such cells expressing CTLA-4, we demonstrate that indeed CTLA-4 is involved in CD4+CD25+CD152+ T,cell regulatory activity, while suppressive cytokines are not. [source] Cytotoxic T lymphocyte associated antigen-4 exon 1 A/G polymorphism in Iranian patients with multiple sclerosisEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2008A. Borhani Haghighi Background:, Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a T-cell surface receptor of activated T cells. Material and methods:, We studied 100 Iranian patients with clinically definite multiple sclerosis (MS) and 100 ethnic, sex- and age-matched controls. CTLA-4 exon 1 A/G polymorphism was compared amongst patients and controls. Results:, There was no statistically significant difference in the allelic [odds ratio (OR): 1.19, confidence interval (CI) 95%: 0.76,1.85, P = 0.4] and genotypes (OR: 1.60, CI 95%: 0.911,2.824, P = 0.102) distribution amongst patients and controls. Also gender, course and progression index did not reveal any statistically significant differences in allele and genotype distribution of A/G polymorphism. Conclusion:, As a non-European patient population, our results are consistent with the major previous studies showing no significant associations between CTLA4 exon 1 polymorphism and neither MS nor any of its subtypes. [source] Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitisHEPATOLOGY, Issue 1 2000Kosh Agarwal Genetic susceptibility to type 1 autoimmune hepatitis is indicated by a preponderance of female subjects and strong associations with human leukocyte antigens (HLA) DRB1*0301 and DRB1*0401. The gene encoding cytotoxic T-lymphocyte antigen-4 (CTLA-4) on chromosome 2q33 may also influence autoimmunity. To determine the frequency and significance of the exon 1 adenine (A)-guanine (G) base-exchange polymorphism for CTLA-4 in patients with type 1 autoimmune hepatitis, 155 northern European Caucasoid patients and 102 ethnically-matched control subjects were tested by polymerase chain reaction. The genotype distribution was significantly different in patients compared to controls (AA = 50/155 patients vs. 51/102 controls; AG = 84/155 patients vs. 38/102 controls; GG = 21/155 patients vs. 13/102 controls, ,2 = 8.94, P = .011). This difference was caused by a significant over-representation of the G allele in patients compared to controls (105/155 patients vs. 51/102 controls, ,2 = 8.34, P = .004, odds ratio = 2.12). The GG genotype was associated with a significantly higher mean serum aspartate transaminase level (P = .03), greater frequency of antibodies to thyroid microsomal antigens (P = .004) and was found more commonly in patients with HLADRB1*0301 (P = .02). Treatment outcomes, however, were not affected by the genotype. The CTLA-4 G allele is more common in patients with type 1 autoimmune hepatitis and may represent a second susceptibility allele. Furthermore, there may be synergy between the HLA-DRB1*0301 and the GG genotype in terms of disease risk. [source] CD28 and CTLA-4 coreceptor expression and signal transductionIMMUNOLOGICAL REVIEWS, Issue 1 2009Christopher E. Rudd Summary:, T-cell activation is mediated by antigen-specific signals from the TCR,/CD3 and CD4,CD8,p56lck complexes in combination with additional co-signals provided by coreceptors such as CD28, inducible costimulator (ICOS), cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death (PD-1), and others. CD28 and ICOS provide positive signals that promote and sustain T-cell responses, while CTLA-4 and PD-1 limit responses. The balance between stimulatory and inhibitory co-signals determines the ultimate nature of T-cell responses where response to foreign pathogen is achieved without excess inflammation and autoimmunity. In this review, we outline the current knowledge of the CD28 and CTLA-4 signaling mechanisms [involving phosphatidylinositol 3 kinase (PI3K), growth factor receptor-bound protein 2 (Grb2), Filamin A, protein kinase C , (PKC,), and phosphatases] that control T-cell immunity. We also present recent findings on T-cell receptor-interacting molecule (TRIM) regulation of CTLA-4 surface expression, and a signaling pathway involving CTLA-4 activation of PI3K and protein kinase B (PKB)/AKT by which cell survival is ensured under conditions of anergy induction. [source] CD28, CTLA-4 and their ligands: who does what and to whom?IMMUNOLOGY, Issue 2 2000D. M. Sansom First page of article [source] IL-23/IL-17 immunity as a hallmark of Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2008Veera Hölttä MD Abstract Background: We studied the balance between ileal T-effector cells versus T-regulatory cells in active and inactive Crohn's disease (CD). Methods: We compared effector and regulatory T-cell-related markers such as interleukin (IL),17, interferon (IFN)-,, IL-4, and Foxp3 transforming growth factor (TGF),, CTLA-4 and markers for innate immune activation such as IL-6, IL-10, IL-18, IL-23, tumor necrosis factor (TNF),,, and IL-12p70, studied with immunohistochemistry and RT-PCR in ileal biopsies from patients with active or inactive CD and from control subjects. IL-17 in fecal samples was detected by ELISA. The effect of IL-17 on IL-8 and TNF-, mRNA expression in epithelial cell line Caco-2 was studied. Results: The numbers of IL-4-, IL-17-, and IL-23(p19)-positive cells in the lamina propria were higher in patients with CD, both active and inactive, than in the controls. mRNA expression of IL-17A, IL-6, and Foxp3 was increased in the biopsies both from patients with active disease and those in remission, whereas mRNA expression of IL-23 was increased only in active disease. Fecal IL-17 concentration was increased in patients with active disease. IL-17 enhanced the IL-8 and TNF-, response of the epithelial cell line to lipopolysaccharide (LPS) in vitro. Conclusions: Our findings suggest that activation of the IL-23/IL-17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS. (Inflamm Bowel Dis 2008) [source] CTLA-4 gene promoter and exon 1 polymorphisms in Iranian patients with gastric and colorectal cancersJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 12 2007Abolghasem Hadinia Abstract Background and Aim:, Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down-regulating T-cell activation. Effects of several polymorphisms in CTLA-4 on CTLA-4 expression and function have been previously documented. The aim of this study was to investigate the putative effect of CTLA-4 polymorphisms on susceptibility to gastric and colorectal cancers in an Iranian population. Methods:, A total of 155 patients (109 with colorectal cancer and 46 with gastric cancer) and 190 age- and sex-matched healthy controls were evaluated. Genotyping of ,1722T/C, ,1661A/G, and +49A/G were performed by PCR restriction fragment length polymorphism methods and of ,318C/T by a PCR amplification refractory mutation system technique. Results:, No statistically significant differences were found in the genotype distribution and allele frequencies among patients and controls. Haplotype analysis demonstrated that the TACG haplotype (,1722T, ,1661A, ,318C, +49G) frequency was significant increased in patients with colorectal cancer (P = 0.009) and gastric cancer (P = 0.006) in comparison to the control group. In contrast, the TACA haplotype frequency was significantly decreased in patients with colorectal cancer (P = 0.02) and not significantly decreased in patients with gastric cancer (P = 0.13) compared to the control group. Conclusion:, A positive association between CTLA-4 TACG haplotype and gastric and colorectal cancers was found in an Iranian population. A protective role for TACA haplotype is postulated. [source] Association of CTLA-4 gene polymorphism with oral submucous fibrosis in TaiwanJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 4 2004Yi-Ning Shin Background:, Oral submucous fibrosis (OSF) is an insidious, pre-cancerous, chronic disease that may affect the entire oral cavity and sometimes extend to the pharynx. It has been reported to be associated with immune function. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CD (cluster of differentiation) 152) is a negative regulator of T-lymphocyte activation. Particular genotypes of the locus encoding the CTLA-4 glycoprotein have been associated with susceptibility to various autoimmune diseases. This study was designed to investigate the role of CTLA-4 polymorphism in susceptibility to OSF. Methods:, We genotyped 62 patients with OSF and 147 healthy controls for allelic determinants at the exon 1 +49 polymorphism site by restriction fragment length polymorphism. Genotype and phenotype frequencies were evaluated with Chi-squared test. Results:, The G allele at position +49 of exon 1 was significantly associated with OSF. The frequency of A/A homozygotes was higher in controls than in patients (17.0% vs. 3.2%; ,2 = 7.65, P = 0.02); the G phenotype was more frequent in patients than in controls (96.8% vs. 83.0%; ,2 = 9.31, P = 0.002). Compared with controls, the G allele genotype and phenotype frequencies were increased in patients with OSF. Conclusion:, This is the first report that the CTLA-4 +49 G allele confers an increased risk of OSF in Taiwan. [source] Expression Of The Co-Stimulatory Molecule BB-1, The Ligands CTLA-4 and CD28 and Their Mrnas In Chronic Inflammatory Demyelinating PolyneuropathyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2001K Murata To examine whether the Schwann cells in patients with autoimmune neuropathies have the potential to behave as professional antigen-presenting cells, we investigated the expression of the co-stimulatory molecules BB-1, B7-1 (CD80), B7-2 (CD86) and their counter-receptors CD28 or CTLA-4 (CD152) at the protein and mRNA levels in sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), CIDP associated with human immunodeficiency virus infection (HIV-CIDP), IgM paraproteinaemic neuropathy and normal or non-immune axonal neuropathy. In single-and double-labelling experiments, we used the S-100 antigen as a pan-Schwann cell marker, myelin-associated glycoprotein as a marker for myelinating Schwann cells and the fibrillary acidic protein as a marker for unmyelinating Schwann cells. The expression of the B7 family of molecules was limited to BB-1 and was observed only on the Schwann cells. There was constitutive expression of BB-1 on unmyelinating Schwann cells in all nerves studied. However, in CIDP and HIV-CIDP, but not the other diseases, there was prominent upregulation of BB-1 on the myelinating Schwann cells. The endoneurial T cells in the proximity of BB-1-positive Schwann cells expressed the CD28 or CTLA-4 counterreceptors. Reverse transcription-polymerase chain reaction confirmed that these ligands were upregulated only in CIDP. Because the myelinating BB-1-positive Schwann cells expressed HLA-DR antigen, the findings indicate that, in CIDP, Schwann cells possess the necessary markers to function as antigen-presenting cells. [source] Impact of polymorphisms of the major histocompatibility complex class II, interleukin-10, tumor necrosis factor-, and cytotoxic T-lymphocyte antigen-4 genes on inhibitor development in severe hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2009A. PAVLOVA Summary.,Background: Approximately 25% of severe hemophilia A (HA) patients develop antibodies to factor VIII protein. Patients: In the present case-controlled cohort study, 260 severely affected, mutation-type-matched HA patients were studied for association of human leukocyte antigen (HLA) class II molecules and polymorphisms in the genes encoding interleukin-10 (IL-10), tumor necrosis factor-, (TNF-,) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) and development of inhibitors. Results: Our results demonstrate a higher frequency of DRB1*15 and DQB1*0602 alleles as well as of the haplotype DRB1*15/DQB1*0602 in inhibitor patients [odds ratio (OR) 1.9; P < 0.05]. In TNF-,, the A allele of the ,308G>A polymorphism was found with higher frequency in the inhibitor cohort (0.22 vs. 0.13, OR 1.80). This finding was more pronounced for the homozygous A/A genotype (OR 4.7). For IL-10, the ,1082G allele was observed more frequently in patients with inhibitors (0.55 vs. 0.43; P = 0.008). The functional cytokine phenotype was determined for the first time, on the basis of the genetic background, and this showed that 12% of patients with inhibitors were high-TNF-,/high-IL-10 producers, as compared with 3% of non-inhibitor patients (OR 4.4). A trend for a lower frequency of the A allele of the CT60 polymorphism in CTLA-4 was found in inhibitor patients (0.42 vs. 0.50). Conclusions: In conclusion, the reported data clearly highlighted the participation of HLA molecules in inhibitor formation in a large cohort of patients. The higher frequencies of the ,308G>A polymorphism in TNF-, and ,1082A>G in IL-10 in inhibitor patients confirmed the earlier published data. The CT60 single-nucleotide polymorphism in CTLA-4 is of apparently less importance. [source] Effect of soluble form CTLA-4 on spontaneous IgA nephropathy in ddY miceNEPHROLOGY, Issue 2001K Okano The aim of the present study was to examine the role of CD28-B7 signalling in the development of glomerulonephritis in ddY mice, an animal model for IgA nephropathy. To achieve this aim, we investigated whether the CTLA-4 (CD152) fusion protein, which binds to B7.1 (CD80) and B7.2 (CD86), affects glomerular pathological changes (including IgA deposition), or functional parameters (such as serum creatinine and proteinuria). Each group (n = 4) was given either human CTLA-4 fused with human IgG (CTLA4Ig) or control human IgG1. All treated groups of mice were injected intraperitoneally at a dose of 0.1 mg twice a week for the duration of the study. Mice given control human IgG1 progressively developed typical mesangioproliferative glomerulonephritis, with remarkable glomerular IgA deposits. In contrast, mice treated with CTLA4Ig showed a significant reduction in proteinuria and mesangioproliferative change, with an expansion of the mesangial matrix at 40 weeks of age. The serum IgA levels of these mice were considerably lower than those in mice given the control human IgG1. A direct immunofluorescence study showed the reduction of glomerular IgA deposits in CTLA4Ig-treated mice. We have demonstrated for the first time that the development of spontaneously occurring IgA nephropathy can be prevented in ddY mice by blocking the CD28-B7 interaction using a soluble form of CTLA4Ig. These results suggest that a costimulatory signal via CD28-B7 may play a crucial role in the development and progression of IgA nephropathy. [source] Role for CTLA-4 but not CD25+ T cells during Schistosoma mansoni infection of micePARASITE IMMUNOLOGY, Issue 6 2007C. M. WALSH SUMMARY Schistosoma mansoni infection of mice increases the frequency of cells that are CD4+CD25+ in the acute (4 and 8 weeks) and chronic (16 week) stages of infection. Depletion of > 85% of CD25+ cells in the acute or chronic stages of schistosome infection caused no overt changes in morbidity or immunological responses. The absence of effect in mice with CD25+ cells depleted may be due to the preferential expression of IL-4 and IL-10, two cytokines that are protective in schistosome infection, on CD25, CD4+ cells. We also assessed infection-induced changes of other regulatory markers, GITR, CD103 and CTLA-4 on CD4+ cells. We identified a marked expansion of CTLA-4+ population on CD25, CD4+ cells in acute and chronic infection. Blocking of CTLA-4 during acute, but not chronic infection, caused significant weight loss and altered the type 2 cytokine response of mice, with increased IL-4 and IL-5 production associated with significantly more Th2 cells and eosinophils in the liver granuloma. This study illustrates the complexity of regulation of T cells in schistosome infection and highlights a specific role for CTLA-4+, but not CD25+ cells, in the regulation of Th2 responses in helminth infection. [source] CTLA-4 expression in T cells of patients with atopic dermatitisPEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 5 2005Sung Yon Choi Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is a surface molecule of activated T cells with sequence homologous to CD28, and may act as a negative regulator of T-cell activation. In murine animal models, cross-linkage of CTLA-4 molecules on the cell surface results in decreased T-cell proliferation, accompanied by increased interleukin (IL)-2 production and apotosis. To clarify the activation of peripheral blood T cells, we studied the CTLA-4 expression in 32 patients with atopic dermatitis who visited our institution, and 19 normal children who visited for pre-operative laboratory examination were used as normal controls. Whole blood was obtained from all subjects and stained with anti-CD3, anti-CD4, anti-CD8 monoclonal antibodies (mAb). After erythrocyte lysis with lysing solution, the cells were stained with anti-CTLA-4 mAb, and stained cells were analysed by fluorescence-activated cell sorter (FACScan) flow cytometer. Intracellular expression of CTLA-4 was significantly upregulated in peripheral blood CD3+ T cells (36.8%), CD4+ T cells (21.7%) and CD8+ T cells (18.7%) of patients with atopic dermatitis, compared with normal control (18.3%, 9.7%, 9.8%; respectively). Furthermore, CTLA-4-positive CD3+ T cells in patients with severe atopic dermatitis were significantly higher compared with milder group (42.8% vs. 32.2%). However, no significant difference was obtained in CD4+ and CD8+ T cells. Mean percentage of T cells expressing CTLA-4 in patients with atopic dermatitis was higher than the control group. These observations suggest the possibility that the disease activity can be correlated with the CTLA-4 level. [source] Effects of inhaled fluticasone propionate on CTLA-4-positive CD4+CD25+ cells in induced sputum in mild asthmaticsRESPIROLOGY, Issue 7 2008Tomotaka KAWAYAMA Background and objective: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) signalling of regulatory T cells regulates mucosal lymphocyte tolerance and differentiation, and may therefore have a beneficial effect in allergic diseases such as asthma. The aim of this study was to evaluate the effects of fluticasone propionate (FP) on CD4+CD25+ T cell co-expression of CTLA-4 in the sputum of mild asthmatic subjects. Methods: Eleven mild, stable asthmatic subjects completed a double-blind, randomized, cross-over, placebo-controlled study to compare the effects of 14 days 200 µg twice daily FP and placebo. Before and after treatment, airway hyperresponsiveness was measured, and sputum was induced for measurements of CTLA-4+CD4+CD25+ cells, eosinophils and levels of IL-10, IL-13 and transforming growth factor (TGF)-, Results: FP treatment increased co-expression of CTLA-4 on sputum CD4+CD25+ cells from a mean (SEM) of 7.9% (1.8) to 12.7% (3.3) after 14 days treatment (P < 0.05) compared with placebo. FP treatment also significantly increased IL-10 levels, reduced per cent sputum eosinophils, and reduced airway hyperresponsiveness (P < 0.05). There was a significant negative correlation between the change in airway hyperresponsiveness and per cent sputum eosinophils (P < 0.01), but no correlation with changes in CTLA-4+CD4+CD25+ cells (P > 0.05). There was no change in the levels of sputum IL-13 or TGF-, Conclusions: The percentage of airway CTLA-4+CD4+CD25+ cells increased after FP treatment, coincident with improvements in airway inflammation and hyperresponsiveness. Whether improved asthma assessments are related to the increase in CTLA-4+CD4+CD25+ cells and thus improved regulation of T-cell tolerance and differentiation will require a larger sample size to determine. The normalization of CTLA-4+CD4+CD25+ cells in asthma may contribute to the management of this disease. [source] ORIGINAL ARTICLE: PD-1 but not CTLA-4 Blockage Abrogates the Protective Effect of Regulatory T Cells in a Pregnancy Murine ModelAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2009Paul Ojiambo Wafula Problem, Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect paternal/fetal antigens from rejection by maternal effector cells. Accordingly, the transfer of Treg obtained from BALB/c-mated CBA/J females prevents abortion in DBA/2J-mated animals. The actual mechanism through which Treg mediate their protective effect is still inconclusive. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and Programmed cell death 1 (PD-1) are some of known Treg-associated molecules; however, their role in Treg-mediated fetal protection in murine model has not been investigated. Method of study, Treg obtained from normal pregnant animals (NP; CBA/J × BALB/c) on day 14 were adoptively transferred into abortion-prone mice (AP; CBA/J × DBA/2J) intravenously on day 2 of pregnancy. An amount of 250 ,g of either anti-PD-1 or anti-CTLA-4 mAb were injected intraperitoneally on days 0, 3, 6 and 9 of pregnancy. Controls received Treg + IgG or Treg + PBS. NP or AP treated with PBS served as additional controls. Results, Blocking PD-1 abrogated the protective effect of Treg, resulting in a higher median abortion rate in comparison with the Treg/isotype-treated control while CTLA-4 blockage did not interfere with the protective effect of Treg. This was associated with a diminished number of vascular endothelial growth factor-A+ cells, previously reported as stimulators of lymphocyte extravasation in preterm labor. Conclusion, Our data suggest PD-1 as an important mediator in Treg-induced fetal protection in the CBA/J × DBA/2J murine model. [source] Recipient CTLA-4 +49 G/G Genotype Is Associated with Reduced Incidence of Acute Rejection After Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2003Philip de Reuver The aim of this pilot study was to investigate whether acute rejection after liver transplantation is associated with known single-nucleotide polymorphisms (SNPs) in the CD86- and CTLA-4 genes of liver-transplant donors and recipients. Single nucleotide polymorphisms were determined in 135 liver transplant recipients and in 73 donors. Acute rejection was not associated with CD86 + 1057 G/A genotype distributions in donors and in recipients. In univariate analysis recipient CTLA-4 ,318 G/T and + 49 A/G genotype distributions were both weakly associated with acute rejection. Multivariate analysis revealed that the CTLA-4 + 49 SNP, but not the ,318 SNP, was independently of other risk factors associated with acute rejection. Only one out of 13 CTLA-4 + 49 G-homozygotes (8%) experienced acute rejection(s) compared with 40% of A/A or A/G recipients. The CTLA-4 + 49 A/G SNP, which results in an amino acid substitution in the signal peptide of the protein, did not, however, affect intracellular expression or trafficking of CTLA-4 in T cells, nor soluble serum CTLA-4 concentrations of the liver transplant recipients. In conclusion, this pilot study suggests that liver transplant recipients homozygous for CTLA-4 + 49 G have a reduced risk of acute rejection. [source] Genetic interaction of CTLA-4 with HLA-DR15 in multiple sclerosis patients,ANNALS OF NEUROLOGY, Issue 1 2003Mehdi Alizadeh PhD Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a genetic component. Until now, the more consistent association with the disease is found with the major histocompatibility complex, especially HLA-DRB1*1501-DQB1*0602 haplotype. In this report, we demonstrate the interaction of Cytotoxic T Lymphocyte-associated antigen 4 (CTLA-4 [CD152]) gene with DRB1*15 haplotype in multiple sclerosis genetic susceptibility. Our data were obtained from two European independent family-based studies including 610 multiple sclerosis family trios. Ann Neurol 2003;54:119,122 [source] CTLA-4 (CD152) controls homeostasis and suppressive capacity of regulatory T cells in miceARTHRITIS & RHEUMATISM, Issue 1 2009Paula Kolar Objective CD4+CD25+ regulatory T cells (known as Treg cells) suppress unwanted and autoreactive T cell responses. Treg cells express the costimulatory molecule CTLA-4 intracellularly, but the mechanisms by which Treg cells exploit CTLA-4 signaling remain unclear. The present study was undertaken to investigate the role of CTLA-4 in controlling the homeostasis and suppressive function of Treg cells. Methods Murine Treg cells were analyzed by flow cytometry for coexpression of CTLA-4 and typical Treg cell,expressed molecules, and the influence of CTLA-4 on T cell proliferation, suppression, and apoptosis was investigated by in vitro assays. To analyze the importance of CTLA-4 in Treg cell,mediated suppression in vivo, wild-type Treg cells were transferred into CTLA-4,deficient mice displaying lymphoproliferation, and survival was monitored over time. Results A strong correlation between expression of forkhead box P3 and ex vivo expression of CTLA-4 in Treg cells was observed. Inhibition of CTLA-4 signaling in Treg cells during in vitro stimulation increased cell cycling and led to enhanced activation-induced cell death (AICD), which was mediated by CD95/CD95 ligand,induced activation of caspases. Blockade of CTLA-4 signaling resulted in impairment of the suppressive capacity of Treg cells. Despite these effects, high amounts of Treg cells persisted in CTLA-4,deficient mice. Results of transfer experiments in CTLA-4,deficient mice showed that the mice had a significantly prolonged lifespan when CTLA-4,competent Treg cells were injected. Conclusion Expression of CTLA-4 on Treg cells serves to control T cell proliferation, to confer resistance against AICD, and to maintain the suppressive function of Treg cells. [source] Overcoming immunological tolerance to melanoma: Targeting CTLA-4ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2010F Stephen HODI Abstract The use of immunotherapeutics in melanoma has received much attention, and recent advances to further characterize the regulatory components of the immune system and the importance of co-stimulatory molecules have opened a new area for clinical investigation. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves as a negative regulator of immunity. Recent trials administering fully human anti-CTLA-4 monoclonal antibodies to melanoma patients have demonstrated clinically meaningful responses. Treatment with CTLA-4 blocking antibodies, however, is not without potential toxicities. Autoimmune side-effects, the most common being colitis-associated diarrhea, are frequently associated with clinical responses. In efforts to build upon prior vaccination efforts as well as attempt to offer patients clinically meaningful immune responses with a CTLA-4 blockade but without significant toxicities, we conducted a clinical trial in patients who previously received autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GVAX; Cell Genesys, South San Francisco, CA, USA) with periodic infusions of CTLA-4 blocking antibodies. This sequential treatment resulted in clinically significant anti-tumor immunity without grade 3 or 4 toxicity in most patients. Pathological analyses following treatment of pre-existing tumors revealed a linear correlation between tumor necrosis and the ratio of intra-tumoral CD8+ effector cells to FoxP3+ regulatory cells (Tregs). Effective anti-tumor immunity and serious autoimmunity can be disassociated. Further targeting of anti-tumor Tregsin combinatorial therapy approaches may be a rich avenue of future investigation. [source] Inhibition of human allergic T-helper type 2 immune responses by induced regulatory T cells requires the combination of interleukin-10-treated dendritic cells and transforming growth factor-, for their inductionCLINICAL & EXPERIMENTAL ALLERGY, Issue 12 2006I Bellinghausen Summary Background In grass pollen-allergic individuals, T cell anergy can be induced by IL-10-treated dendritic cells (IL-10-DC) resulting in the suppression of T helper type 1 (Th1) as well as Th2 cells. This study was performed to analyse whether such IL-10-DC-treated T cells are able to act as regulatory T cells (Treg) suppressing the function of other T cells in the periphery. As transforming growth factor (TGF)-, is also a potential inducer of Treg, we additionally analysed the inhibitory capacity of TGF-,-treated T cells in this system. Materials and Methods Freshly isolated CD4+ or CD4+CD25, T cells from grass pollen-allergic donors were stimulated with autologous mature monocyte-derived allergen-pulsed DC in the presence or absence of T cells previously cultured with IL-10-DC- and/or TGF-,. Results Anergic T cells induced by allergen-pulsed IL-10-treated DC or allergen-pulsed DC and TGF-, enhanced IL-10 production and strongly inhibited IFN-, production of freshly prepared peripheral CD4+ or CD4+CD25, T cells while proliferation and Th2 cytokine production were only slightly reduced. The combination of allergen-pulsed IL-10-treated DC and TGF-, had an additional effect leading to a significant suppression also of Th2 cytokine production and proliferation. Suppression was not antigen-specific and was mainly mediated by cell-to-cell contact and by the molecule-programmed death-1 and only partially by CTLA-4, TGF-, and IL-10. Conclusion These data demonstrate that regulatory T cells that also suppress Th2 cytokine production are induced by two signals: TGF-, and IL-10-DC. This is of importance for the regulation of allergic immune responses and might be exploited for future therapeutic strategies for allergic diseases. [source] Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasiaCLINICAL & EXPERIMENTAL IMMUNOLOGY, Issue 2 2007J. Visser Summary Oncogenic human papillomavirus (HPV)-infection is crucial for developing cervical cancer and its precursor lesions [cervical intraepithelial neoplasia (CIN)]. Regulatory T cells (Tregs) might be involved in the failure of the immune system to control the development of HPV-induced cancer. We investigated frequencies, phenotype and activity of Tregs in patients with cervical neoplasia. CIN and cervical cancer patients showed increased CD4+/CD25high T cell frequencies in peripheral blood and CD4+ T cell fraction. These CD4+/CD25high T cells represent Tregs as demonstrated by their low proliferation rate, low interferon (IFN)-,/interleukin (IL)-10 ratio, high expression of CD45RO, GITR, CTLA-4, forkhead box P3 (FoxP3) and low CD45RA expression. Moreover, in HPV16+ cervical cancer patients, in-vitro depletion of CD25+ T cells resulted in increased IFN-, T cell responses against HPV16 E6- and E7 peptides. Thus, increased frequencies of Tregs in cervical cancer patients may indeed suppress HPV-specific immunity. Longitudinal analysis of CD4+/CD25high T cell frequencies in patients showed a modest decline 1 year after curative surgery or chemoradiation. This study demonstrates increased frequencies and suppressive activity of Tregs in cervical cancer. These results imply that Tregs may suppress the immune control of cervical neoplasia and furthermore that suppression of immunity by Tregs will be another hurdle to overcome in therapeutic immunization strategies against cervical neoplasia. 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