929 resultados para CD4 CD25 regulatorische T-Zellen, FoxP3 GITR, Autoimmunität, Toleranz, T-Zell-Homeostase
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Intraperitoneal proliferation of the metacestode stage of Echinococcus multilocularis in experimentally infected mice is followed by an impaired host immune response favoring parasite survival. We here demonstrate that infection in chronically infected mice was associated with a 3-fold increase of the percentages of CD4+ and CD8+ peritoneal T (pT) cells compared to uninfected controls. pT cells of infected mice expressed high levels of IL-4 mRNA, while only low amounts of IFN-gamma mRNA were detected, suggesting that a Th2-biased immune response predominated the late stage of disease. Peritoneal dendritic cells from infected mice (AE-pDCs) expressed high levels of TGF-beta mRNA and very low levels of IL-10 and IL-12 (p40) mRNA, and the expression of surface markers for DC-maturation such as MHC class II (Ia) molecules, CD80, CD86 and CD40 was down-regulated. In contrast to pDCs from non-infected mice, AE-pDCs did not enhance Concanavalin A (ConA)-induced proliferation when added to CD4+ pT and CD8+ pT cells of infected and non-infected mice, respectively. In addition, in the presence of a constant number of pDCs from non-infected mice, the proliferation of CD4+ pT cells obtained from infected animals to stimulation with ConA was lower when compared to the responses of CD4+ pT cells obtained from non-infected mice. This indicated that regulatory T cells (Treg) may interfere in the complex immunological host response to infection. Indeed, a subpopulation of regulatory CD4+ CD25+ pT cells isolated from E. multilocularis-infected mice reduced ConA-driven proliferation of CD4+ pT cells. The high expression levels of Foxp3 mRNA by CD4+ and CD8+ pT cells suggested that subpopulations of regulatory CD4+ Foxp3+ and CD8+ Foxp3+ T cells were involved in modulating the immune responses within the peritoneal cavity of E. multilocularis-infected mice.
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BACKGROUND Insect bite hypersensitivity (IBH) is a recurrent allergic dermatitis of horses with similarities to human atopic eczema, caused by bites of insects of the genus Culicoides. Previous studies suggested a dysregulated T cell tolerance to Culicoides allergen in IBH-affected horses. OBJECTIVE We have investigated whether the suppressive function of CD4(+) CD25(high) cells is impaired in IBH-affected horses and possible ways to restore it. METHODS CD4(+) CD25(-) cells sorted from peripheral blood mononuclear cells (PBMC) were stimulated with irradiated autologous PBMC pulsed with Culicoides or tetanus toxoid as control antigen, in the presence of CD4(+) CD25(high) cells. Furthermore, Culicoides-specific CD4(+) CD25(high) regulatory cells were expanded or induced from CD4(+) CD25(-) cells in vitro in the presence of a combination of rIL-2 and rTGF-1 (rIL-2/rTGF-1) or of retinoic acid and rapamycin (RetA/Rapa). Proliferation was determined by [(3) H] thymidine incorporation and cytokine production measured by flow cytometry. RESULTS The ability of Culicoides- but not tetanus-stimulated CD4(+) CD25(high) cells to suppress proliferation of CD4(+) CD25(-) cells was significantly lower in IBH-affected horses (28%) than in healthy controls (86%). The decreased suppression in IBH-affected horses was associated with a significantly higher proportion of IL-4(+) cells and a lower percentage of FoxP3(+) IL-10(+) compared to controls. Addition of rIL-2/rTGF-1 or of RetA/Rapa to Culicoides-stimulated CD4(+) CD25(high) cells from IBH-affected horses significantly increased the proportion of FoxP3(+) IL-10(+) cells. We also found that RetA/Rapa induced a more significant decrease in the frequency of IL-4(+) cells than rIL-2/rTGF-1. Moreover, the suppressive activity of Culicoides-stimulated CD4(+) CD25(high) cells was significantly restored by both rIL-2/rTGF-1and RetA/Rapa, albeit in an antigen-unspecific manner. In contrast, in vitro induced Culicoides-specific CD4(+) CD25(high) cells suppressed proliferation of CD4(+) CD25(-) cells in an antigen-specific manner. CONCLUSION AND CLINICAL RELEVANCE The in vitro induction of functional allergen-specific Treg cells in IBH-affected horses suggests a potential therapeutic use of these cells in allergy.
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INTRODUO: A infeco por HIV-1 um grave problema de sade pblica causando elevada taxa de morbidade e mortalidade. Entretanto, alguns indivduos so considerados resistentes infeco por HIV-1, mesmo aps repetidas exposies ao vrus. Vrios fatores imunolgicos e genticos podem estar associados a resistncia infeco, como ativao de componentes da imunidade inata e tambm devido ao baixo perfil de ativao das clulas T. possvel que nos indivduos expostos e no infectados por HIV-1 (ENI) ocorra uma importante atuao das clulas T secretoras de IL-17 e IL-22, e tambm as clulas T reguladoras, pois so necessrias para a manuteno e homeostase das mucosas associadas ao intestino (GALT). OBJETIVO: Avaliar o fentipo e a funo de clulas TCD4+ e TCD8+ em casais sorodiscordante ao HIV-1, compostos por indivduos ENI e os parceiros infectados por HIV-1. MTODOS: Os casais sorodiscordantes ao HIV-1, consistiam de 23 indivduos expostos no-infectados (ENI), 14 mulheres e 9 homens, com mediana de 41 anos e 21 parceiros infectados por HIV-1 (HIV), 20 homens e 1 mulher com mediana de 41 anos. Os controles saudveis foram 24 indivduos (14 mulheres e 10 homens) com mediana de 37 anos. Os casais sorodiscordantes foram compostos por 16 heterossexuais e 7 homossexuais, com tempo de relacionamento de 13 anos. As frequncias de clulas Th17, Th22 e Tc22, as clulas T polifuncionais foram analisadas em clulas mononucleares (CMNs) do sangue perifrico, estimulados com peptdeos da regio Gag do HIV-1 e da enterotoxina B do Staphylococcus aureus (SEB), a frequncia de clulas T reguladoras, o perfil fenotpico de exausto/diferenciao e a expresso da integrina alfa4?7 e CCR9 em clulas T, foram realizados por citometria de fluxo. RESULTADOS: No grupo HIV, as clulas T CD4+ e CD8+ do sangue perifrico mostrou maior frequncia de CD95 e PD-1 e baixa expresso de CD127 comparado ao grupo ENI e controle. A frequncia de clulas Th17 em CMNs aumentou nos grupos ENI e HIV-1 na condio sem estmulo, contudo, aps estmulo com os peptdeos da regio p24 da Gag do HIV-1 induziu resposta somente no grupo HIV-1. O grupo ENI mostrou resposta antgeno-especifica somente para IL-22. Alm disto, avaliando as clulas Tc22 e Th22, foi verificado aumento da resposta aos peptdeos da Gag e tambm ao SEB, nos grupos HIV e ENI. A presena de clulas T polifuncionais antgeno-especificas, secretoras de 5-4 citocinas, foi detectada apenas em clulas T CD38+ no grupo HIV, enquanto os indivduos ENI mostraram resposta polifuncional por clulas T CD38- somente ao estmulo policlonal por SEB. Uma diminuio do nmero absoluto de clulas T reguladoras (CD4+CD25+CD127low/-Foxp3+) foi detectada no grupo HIV comparado ao ENI e controle, com maior expresso de molculas HLA-DR e CD95. Alm disto, foi detectado diminuio na frequncia de clulas TCD8+ ?4?7+ no grupo ENI e de clulas TCD4+ alfa4beta7+ nos grupos ENI e HIV. Houve uma correlao positiva entre as clulas Tc22 e Th22 com as clulas TCD8+ e TCD4+ que expressam alfa4beta7, no grupo ENI e HIV-1. CONCLUSO: Os indivduos ENI so capazes de desenvolver resposta antgeno-especficas relacionadas com a IL-22, que possui importante funo na imunidade de mucosas. Alm disto, mostram presena de clulas T polifuncionais com baixo perfil de ativao a estmulo policlonal. Os dados evidenciam que os indivduos ENI, mostram induo de clulas Tc22, aumento de expresso de molculas de migrao para o intestino e equilbrio entre as clulas efetoras e Treg, que em conjunto, devem exercer importante papel para a resistncia infeco por HIV-1
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In human systemic lupus erythematosus (SLE), diverse autoantibodies accumulate over years before disease manifestation. Unaffected relatives of SLE patients frequently share a sustained production of autoantibodies with indiscriminable specificity, usually without ever acquiring the disease. We studied relations of IgG autoantibody profiles and peripheral blood activated regulatory T-cells (aTregs), represented by CD4(+)CD25(bright) T-cells that were regularly 70-90% Foxp3(+). We found consistent positive correlations of broad-range as well as specific SLE-associated IgG with aTreg frequencies within unaffected relatives, but not patients or unrelated controls. Our interpretation: unaffected relatives with shared genetic factors compensated pathogenic effects by aTregs engaged in parallel with the individual autoantibody production. To study this further, we applied a novel analytic approach named coreferentiality that tests the indirect relatedness of parameters in respect to multivariate phenotype data. Results show that independently of their direct correlation, aTreg frequencies and specific SLE-associated IgG were likely functionally related in unaffected relatives: they significantly parallelled each other in their relations to broad-range immunoblot autoantibody profiles. In unaffected relatives, we also found coreferential effects of genetic variation in the loci encoding IL-2 and CD25. A model of CD25 functional genetic effects constructed by coreferentiality maximization suggests that IL-2-CD25 interaction, likely stimulating aTregs in unaffected relatives, had an opposed effect in SLE patients, presumably triggering primarily T-effector cells in this group. Coreferentiality modeling as we do it here could also be useful in other contexts, particularly to explore combined functional genetic effects.
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Foxp3 es un marcador clave para identificacin y funcin clulas T reguladoras, adems su expresin se ha observado en diferentes lneas celulares de cncer. El objetivo de este estudio fue determinar si la expresin de Foxp3 en clulas de melanoma murino acta como un mecanismo de evasin de la respuesta inmune tumoral, modificando citocinas involucradas en la fase de inmunoedicin de cncer y promoviendo la generacin de clulas Treg. En este estudio se determin por primera vez la expresin de Foxp3 en las clulas melanoma murino B16F10 wt, y diseamos RNA de interferencia en contra de Foxp3, adems de analizar la expresin de CD25 y produccin de IL-2, INF-, TGF- e IL-10 para determinar su papel in vitro. Para la evaluacin del efecto de Foxp3 durante el desarrollo tumoral in vivo, se estableci una lnea celular con silenciamiento de Foxp3 la cul identificamos como B16F10.DMH1 y se montaron dos modelos de melanoma murino, uno inducido con clulas B16F10 wt y otro inducido con clulas B16F10.DMH1, y se analiz progresin tumoral, produccin de citocinas, expresin de CD25, Foxp3 y poblaciones celulares CD4+ , CD4+CD25+ y CD4+CD25+ Foxp3+ en TILs y clulas de bazo. Nuestros resultados in vitro demuestran que las clulas B16F10 wt expresan Foxp3 a nivel de RNAm y protena, y su localizacin celular es principalmente perinuclear, adems se encontr que estas clulas expresan CD25, y una produccin de citocinas del tipo INF-, TGF-, IL-10 e IL-2. Se encontr que la expresin de Foxp3 afecta la proliferacin en clulas B16F10, encontrando una correlacin positiva entre la expresin de Foxp3, CD25 e IL-2. In vivo, el silenciamiento de Foxp3 en las clulas B16F10.DMH1 afect el desarrollo del melanoma incrementando el tiempo de aparicin de tumor, sobrevida y disminuyendo el peso de los tumores, encontrando una correlacin positiva entre Foxp3, CD25, IL-2 e IL-10 y negativa con la produccin de IFN-, adems se determin que Foxp3 intratumoral est correlacionado con la expresin y presencia de clulas Treg con fenotipo CD4+CD25+ Foxp3+ en el microambiente tumoral y con una disminucin de clulas T CD4+ a nivel perifrico, sin afectar a linfocitos T activados (CD4+CD25+ ). Estos datos sugieren que Foxp3, participa en el desarrollo de la tumorognesis en melanoma murino in vitro e in vivo, con la capacidad de modular a citocinas, molculas involucradas en el desarrollo tumoral, as como poblaciones celulares con fenotipo regulador en el tumor, pero no en periferia.
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Aims: To gain insight on the immunological processes behind cows milk allergy (CMA) and the development of oral tolerance. To furthermore investigate the associations of HLA II and filaggrin genotypes with humoral responses to early oral antigens. Methods: The study population was from a cohort of 6209 healthy, full-term infants who in a double-blind randomized trial received supplementary feeding at maternity hospitals (mean duration 4 days): cows milk (CM) formula, extensively hydrolyzed whey formula or donor breast milk. Infants who developed CM associated symptoms that subsided during elimination diet (n=223) underwent an open oral CM challenge (at mean age 7 months). The challenge was negative in 112, and in 111 it confirmed CMA, which was IgE-mediated in 83. Patients with CMA were followed until recovery, and 94 of them participated in a follow-up study at age 8-9 years. We investigated serum samples at diagnosis (mean age 7 months, n=111), one year later (19 months, n=101) and at follow-up (8.6 years, n=85). At follow-up, also 76 children randomly selected from the original cohort and without CM associated symptoms were included. We measured CM specific IgE levels with UniCAP (Phadia, Uppsala, Sweden), and -lactoglobulin, -casein and ovalbumin specific IgA, IgG1, IgG4 and IgG levels with enzyme-linked immunosorbent assay in sera. We applied a microarray based immunoassay to measure the binding of IgE, IgG4 and IgA serum antibodies to sequential epitopes derived from five major CM proteins at the three time points in 11 patients with active IgE-mediated CMA at age 8-9 years and in 12 patients who had recovered from IgE-mediated CMA by age 3 years. We used bioinformatic methods to analyze the microarray data. We studied T cell expression profile in peripheral blood mononuclear cell (PBMC) samples from 57 children aged 5-12 years (median 8.3): 16 with active CMA, 20 who had recovered from CMA by age 3 years, 21 non-atopic control subjects. Following in vitro -lactoglobulin stimulation, we measured the mRNA expression in PBMCs of 12 T-cell markers (T-bet, GATA-3, IFN-, CTLA4, IL-10, IL-16, TGF-, FOXP3, Nfat-C2, TIM3, TIM4, STIM-1) with quantitative real time polymerase chain reaction, and the protein expression of CD4, CD25, CD127, FoxP3 with flow cytometry. To optimally distinguish the three study groups, we performed artificial neural networks with exhaustive search for all marker combinations. For genetic associations with specific humoral responses, we analyzed 14 HLA class II haplotypes, the PTPN22 1858 SNP (R620W allele) and 5 known filaggrin null mutations from blood samples of 87 patients with CMA and 76 control subjects (age 8.0-9.3 years). Results: High IgG and IgG4 levels to -lactoglobulin and -casein were associated with the HLA (DR15)-DQB1*0602 haplotype in patients with CMA, but not in control subjects. Conversely, (DR1/10)-DQB1*0501 was associated with lower IgG and IgG4 levels to these CM antigens, and to ovalbumin, most significantly among control subjects. Infants with IgE-mediated CMA had lower -lactoglobulin and -casein specific IgG1, IgG4 and IgG levels (p<0.05) at diagnosis than infants with non-IgE-mediated CMA or control subjects. When CMA persisted beyond age 8 years, CM specific IgE levels were higher at all three time points investigated and IgE epitope binding pattern remained stable (p<0.001) compared with recovery from CMA by age 3 years. Patients with persisting CMA at 8-9 years had lower serum IgA levels to -lactoglobulin at diagnosis (p=0.01), and lower IgG4 levels to -lactoglobulin (p=0.04) and -casein (p=0.05) at follow-up compared with patients who recovered by age 3 years. In early recovery, signal of IgG4 epitope binding increased while that of IgE decreased over time, and binding patterns of IgE and IgG4 overlapped. In T cell expression profile in response to lactoglobulin, the combination of markers FoxP3, Nfat-C2, IL-16, GATA-3 distinguished patients with persisting CMA most accurately from patients who had become tolerant and from non-atopic subjects. FoxP3 expression at both RNA and protein level was higher in children with CMA compared with non-atopic children. Conclusions: Genetic factors (the HLA II genotype) are associated with humoral responses to early food allergens. High CM specific IgE levels predict persistence of CMA. Development of tolerance is associated with higher specific IgA and IgG4 levels and lower specific IgE levels, with decreased CM epitope binding by IgE and concurrent increase in corresponding epitope binding by IgG4. Both Th2 and Treg pathways are activated upon CM antigen stimulation in patients with CMA. In the clinical management of CMA, HLA II or filaggrin genotyping are not applicable, whereas the measurement of CM specific antibodies may assist in estimating the prognosis.
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CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance. Intravenous immunoglobulin (IVIg), a therapeutic preparation of normal pooled human IgG, expands Tregs in various experimental models and in patients. However, the cellular and molecular mechanisms by which IVIg expands Tregs are relatively unknown. As Treg expansion in the periphery requires signaling by antigen-presenting cells such as dendritic cells (DCs) and IVIg has been demonstrated to modulate DC functions, we hypothesized that IVIg induces distinct signaling events in DCs that subsequently mediate Treg expansion. We demonstrate that IVIg expands Tregs via induction of cyclooxygenase (COX)-2-dependent prostaglandin E2 (PGE(2)) in human DCs. However, costimulatory molecules of DCs such as programmed death ligands, OX40 ligand, and inducible T-cell costimulator ligands were not implicated. Inhibition of PGE(2) synthesis by COX-2 inhibitors prevented IVIg-mediated Treg expansion in vitro and significantly diminished IVIg-mediated Treg expansion in vivo and protection from disease in experimental autoimmune encephalomyelitis model. IVIg-mediated COX-2 expression, PGE(2) production, and Treg expansion were mediated in part via interaction of IVIg and F(ab('))(2) fragments of IVIg with DC-specific intercellular adhesion molecule-3-grabbing nonintegrin. Our results thus uncover novel cellular and molecular mechanism by which IVIg expands Tregs.
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CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E-2 (PGE(2)) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive transcription factor GLI1 directly arbitrated COX-2 transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.
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3%66.4%.RT-PCR,tsCD25 mRNA,PMA ionomycin .tsCD25,CD4+CD25+Tregs.
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CD4+CD25+T1995TTreg HIV/SIVAIDSTregTregHIV/SIVCD4+CD25+TSIVSIVmac239SIV1DNA19900399083SIVTCD4+TCD8+TCD4/CD8SIVSIVmac2394CD4+CD25+TTregTregSIVCD4+TTregSIVFoxP3 mRNATGF-IL-10SIVTreg TregCCR5HIVCD4HIV/SIVTregTregSIVTregTregCD4+CD25TTregSIVTregTregTregSIVSIVp27
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Despite studies demonstrating that inhibition of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has significant chemotherapeutic benefits in vitro and in vivo, inhibition of COX enzymes is associated with serious gastrointestinal and cardiovascular side effects, limiting the clinical utility of these drugs. PGE2 signals through four different receptors (EP1EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. Here, we show that targeted inhibition of the EP1 receptor in the tumor cells and the tumor microenvironment resulted in the significant inhibition of tumor growth in vivo. Both dietary administration and direct injection of the EP1 receptor-specific antagonist, ONO-8713, effectively reduced the growth of established CT26 tumors in BALB/c mice, with suppression of the EP1 receptor in the tumor cells alone less effective in reducing tumor growth. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor-induced immune suppression. In particular, tumor infiltration by CD4+CD25+Foxp3+ regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased. F4/80+ macrophage infiltration was also decreased; however, there was no change in macrophage phenotype. These findings suggest that the EP1 receptor represents a potential target for the treatment of colon cancer.
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Previously, we demonstrated that alemtuzumab induction with rapamycin as sole maintenance therapy is associated with an increased incidence of humoral rejection in human kidney transplant patients. To investigate the role of rapamycin in posttransplant humoral responses after T cell depletion, fully MHC mismatched hearts were transplanted into hCD52Tg mice, followed by alemtuzumab treatment with or without a short course of rapamycin. While untreated hCD52Tg recipients acutely rejected B6 hearts (n = 12), hCD52Tg recipients treated with alemtuzumab alone or in conjunction with rapamycin showed a lack of acute rejection (MST > 100). However, additional rapamycin showed a reduced beating quality over time and increased incidence of vasculopathy. Furthermore, rapamycin supplementation showed an increased serum donor-specific antibodies (DSA) level compared to alemtuzumab alone at postoperation days 50 and 100. Surprisingly, additional rapamycin treatment significantly reduced CD4(+) CD25(+) FoxP3(+) T reg cell numbers during treatment. On the contrary, ICOS(+) PD-1(+) CD4 follicular helper T cells in the lymph nodes were significantly increased. Interestingly, CTLA4-Ig supplementation in conjunction with rapamycin corrected rapamycin-induced accelerated posttransplant humoral response by directly modulating Tfh cells but not Treg cells. This suggests that rapamycin after T cell depletion could affect Treg cells leading to an increase of Tfh cells and DSA production that can be reversed by CTLA4-Ig.
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RATIONALE: Tuberculosis (TB) remains a leading cause of death, and the role of T-cell responses to control Mycobacterium tuberculosis infections is well recognized. Patients with latent TB infection develop strong IFN-gamma responses to the protective antigen heparin-binding hemagglutinin (HBHA), whereas patients with active TB do not. OBJECTIVES: We investigated the mechanism of this difference and evaluated the possible involvement of regulatory T (Treg) cells and/or cytokines in the low HBHA T-cell responses of patients with active TB. METHODS: The impact of anti-transforming growth factor (TGF)-beta and anti-IL-10 antibodies and of Treg cell depletion on the HBHA-induced IFN-gamma secretion was analyzed, and the Treg cell phenotype was characterized by flow cytometry. MEASUREMENTS AND MAIN RESULTS: Although the addition of anti-TGF-beta or anti-IL-10 antibodies had no effect on the HBHA-induced IFN-gamma secretion in patients with active TB, depletion of CD4(+)CD25(high)FOXP3(+) T lymphocytes resulted in the induction by HBHA of IFN-gamma concentrations that reached levels similar to those obtained for latent TB infection. No effect was noted on the early-secreted antigen target-6 or candidin T-cell responses. CONCLUSIONS: Specific CD4(+)CD25(high)FOXP3(+) T cells depress the T-cell-mediated immune responses to the protective mycobacterial antigen HBHA during active TB in humans.
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The mechanisms by which CD4(+)CD25(+)Foxp3(+) T (Treg) cells regulate effector T cells in a transplantation setting and their in vivo homeostasis still remain to be clarified. Using a mouse adoptive transfer model, we analyzed the in vivo expansion, trafficking, and effector function of alloreactive T cells and donor-specific Treg cells, in response to a full-thickness skin allograft. Fluorescent-labeled CD4(+)CD25(-) and antigen-specific Treg cells were transferred alone or co-injected into syngeneic BALB/c-Nude recipients transplanted with skins from (C57BL/6 x BALB/c) F1 donors. Treg cells divided in vivo, migrated and accumulated in the allograft draining lymph nodes as well as within the graft. The co-transfer of Treg cells did not modify the early activation and homing of CD4(+)CD25(-) T cells in secondary lymphoid organs. However, in the presence of Treg cells, alloreactive CD4(+)CD25(-) T cells produced significantly less IFN-gamma and were present in reduced numbers in the secondary lymphoid organs. Furthermore, time-course studies showed that Treg cells were recruited into the allograft at a very early stage after transplantation and effectively prevented the infiltration of effector T cells. In conclusion, suppression of rejection requires the early recruitment to the site of antigenic challenge of donor-specific Treg cells, which then mainly regulate the effector arm of T cell alloresponses.
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Lhpatite autoimmune (HAI) est une maladie grave affectant le foie et prsentant un haut taux de mortalit lorsque non traite. Les traitements disponibles sont efficaces, mais de graves effets secondaires leur sont associs. Ces effets secondaires sont gnralement le rsultat d'une forte immunosuppression et dautres sont spcifiques chaque mdicament. Aucune immunothrapie spcifique nest prsentement disponible pour le traitement de lHAI. Rcemment, un modle murin dHAI a t dvelopp dans notre laboratoire par xnoimmunisation des souris C57BL/6 avec les antignes humains de l'HAI de type 2. Ce modle prsente la plupart des caractristiques biochimiques et cliniques retrouves chez les patients atteints d'HAI de type 2. Dans cette tude, nous avons value lefficacit de deux types de traitement pour lHAI de type 2 laide de notre modle murin. Dans un premier temps, lanticorps anti-CD3 a t tudi en prophylaxie et en traitement. Nous avons montr quune posologie de 5g danti-CD3 i.v. par jour pendant 5 jours conscutifs induit une rmission chez les souris avec HAI de type 2 tablie (traitement). Cette rmission est caractrise par une normalisation des niveaux dalanine aminotransfrase et une diminution significative de linflammation hpatique. Cette rmission semble tre associe une dpltion partielle et transitoire des lymphocytes T CD3+ dans la priphrie et une augmentation des lymphocytes T rgulateurs CD4+, CD25+ et Foxp3+ dans le foie. La mme posologie lorsquelle est applique en prophylaxie na pas russi prvenir lapparition de lHAI de type 2. La deuxime voie de traitement consiste en ladministration par voie intranasale dun forte dose de formiminotransfrase cyclodsaminase murin (mFTCD), un autoantigne reconnu dans lHAI de type 2. Une administration en prophylaxie par voie intranasale de 100g de mFTCD par jour durant 3 jours conscutifs arrive prvenir lHAI de type 2 en diminuant linflammation hpatique au bout de deux semaines post-traitement.