Home About us Contact
|
Home About us Contact | ||
|
|
||
FoxP3+ T Cells (foxp3+ t + cell)
Selected AbstractsAnti tumour necrosis-, therapy increases the number of FOXP3+ regulatory T cells in children affected by Crohn's diseaseIMMUNOLOGY, Issue 2 2008Ida Ricciardelli Summary Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Its pathogenesis is not completely understood, though the prevailing model is that the intestinal flora drives a strong intestinal T helper 1 (Th1)/Th17 type immune response and inflammation in the genetically susceptible host. This leads to overly aggressive T-cell responses to normal bacteria causing tissue damage. Intestinal homeostasis and maintenance of tolerance to harmless antigens in the intestine has been shown to be maintained by CD4+ CD25+ T regulatory cells (Treg) in animal models of inflammatory bowel diseases. Here we investigated whether Infliximab, a chimeric monoclonal antibody directed against tumour necrosis factor (TNF)-, shown to be highly effective in the treatment of CD, has any effect on mucosal CD4+ CD25+ (FOXP3+) Tregs. Colonic mucosal biopsies from children with active Crohn's disease treated in vivo with Infliximab and controls were analysed to determine FOXP3 expression by immunofluorescence and reverse transcription,polymerase chain reaction. We observed that FOXP3+ T cells were significantly reduced in mucosa of CD patients with active disease compared with controls and restored to normal following Infliximab treatment. The frequency of FOXP3+ cells and mRNA expression was significantly increased in CD mucosa from patients treated in vivo with Infliximab compared with CD patients treated with conventional therapies. In conclusion, we show that Infliximab treatment does not solely neutralize soluble TNF-,, but also affects activation and possibly expansion of mucosal regulatory T cells. We suggest that anti TNF-, immunotherapy can also restore mucosal homeostasis in Crohn's disease. [source] Characterising the local immune responses in cervical intraepithelial neoplasia: a cross-sectional and longitudinal analysisBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 13 2008YL Woo Introduction, Immunological competence influences the progression of cervical intraepithelial neoplasia (CIN) to invasive cancer. Information on the local immunological changes during the natural course of CIN is central for the development of new therapies. Objective, This study defines the populations of tissue-infiltrating immune cells in a cross-sectional cohort of different grades of CIN and also in a longitudinal cohort of regressing, persistent and progressing low-grade (LG)-CIN. Design, A cohort of 125 women with LG cytological atypia was recruited, of which 64/125 (51%) women with LG-CIN were followed prospectively for 1 year. Paraffin-embedded entry and exit cervical biopsies were used for immunohistochemistry analysis (CD4, CD8, CD56, FOXP3, CD1a and granzyme B). Results, At recruitment, 74/125 (59%), 39/125 (31%) and 12/125 (10%) women referred with LG smears had histologically proven LG-CIN, high-grade (HG) and normal biopsies, respectively. Seventeen of 64 (24.6%) women with LG-CIN progressed to HG-CIN within 1 year. In both LG-CIN and HG-CIN, the predominant intraepithelial cell population were cytotoxic T cells, while CD4+ and FOXP3+ T cells predominated the stromal compartment. Women with LG-CIN who later on regressed displayed a significantly higher number of cytotoxic (granzyme B+) cells in their entry samples. In addition, the ratio between CD8+ cells and granzyme B+ cells was close to 1, suggesting that all infiltrating CD8+ T cells were highly active. In contrast, this ratio was three-fold lower in women, in whom the lesions persisted or progressed. Conclusions, This study suggests that the early infiltration of lesions by highly cytotoxic effector cells protects against progression. [source] Partial and transient modulation of the CD3,T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic miceIMMUNOLOGY, Issue 1 2010Devangi S. Mehta Summary It has been established that a total of 250 ,g of monoclonal anti-mouse CD3 F(ab,)2 fragments, administered daily (50 ,g per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing , cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab,)2 in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3,T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4+, CD8+ and CD4+ FoxP3+ T cells. Four doses of 2 ,g (total dose 8 ,g) induced 53% remission of diabetes, similarly to the 250 ,g dose regimen, whereas four doses of 1 ,g induced only 16% remission. While the 250 ,g dose regimen produced nearly complete and sustained modulation of the CD3 ,TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4+ and CD8+ T cells decreased, whereas the proportions of CD4+ FoxP3+ T cells increased; these effects were transient. Mice with greater residual ,-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3,TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. [source] Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosisANNALS OF NEUROLOGY, Issue 5 2010Jorge Correale MD Objective The objective of this study was to investigate the role of CD8+ CD25+ FoxP3+ cells during the course of multiple sclerosis (MS). Methods Peripheral blood and cerebrospinal fluid (CSF) CD8+ T-cell clones (TCCs) recognizing autoreactive CD4+ T cells were isolated from 20 MS patients during exacerbations, 15 patients in remission, 15 healthy subjects, and 10 patients with other inflammatory neurological diseases. Characteristics of noncytotoxic CD8+ CD25+ regulatory T cells were studied. Cell phenotype was evaluated using flow cytometry. Cytokine production and phospho-signal transducer and activator of transcription 3 (STAT3) concentration were determined using enzyme-linked immunosorbent assay. To assess 2,3-dioxygenase (IDO) activity on dendritic cells (DCs), kynurenine concentration was measured by high-performance liquid chromatography. Results Inhibition of CD4+ self-reactive T-cell proliferation, and of interferon-, and interleukin (IL)-17 secretion, was observed after adding CD8+ CD25+ FoxP3+ cells to cultures. Suppression was abrogated by silencing FoxP3 using small interfering RNA. Cells were CD122+, CTLA-4+, GITR+, CCR7+, and CD62L+, producing IL-10 and transforming growth factor-,. CD8+ CD25+ FoxP3+ cells downregulated costimulatory molecule expression on dendritic cells through a STAT3-mediated pathway, resulting in less efficient antigen presentation, and induced IDO expression on DCs through STAT3 and cytotoxic T-lymphocyte antigen 4-dependent mechanisms. CD8+ regulatory TCC cloning frequency studied in blood and CSF was suppressed to a greater degree during exacerbations than during remission or in controls. Likewise, in CSF of MS patients during acute exacerbations, lower levels of CD8+ CD25+ FoxP3+ T cells were detected using flow cytometry. Interpretation CD8+ CD25+ FoxP3+ cells are novel regulatory cells exerting significant influence over self-reactive CD4+ T-cell regulation during the course of MS. Induction of these cells may provide new therapeutic alternatives for MS by eliminating or inhibiting self-reactive T cells. ANN NEUROL 2010;67:625,638 [source] Association between parasite infection and immune responses in multiple sclerosisANNALS OF NEUROLOGY, Issue 2 2007Jorge Correale MD Objective To assess whether parasite infection is correlated with a reduced number of exacerbations and altered immune reactivity in multiple sclerosis (MS). Methods A prospective, double-cohort study was performed to assess the clinical course and radiological findings in 12 MS patients presenting associated eosinophilia. All patients presented parasitic infections with positive stool specimens. In all parasite-infected MS patients, the eosinophilia was not present during the 2 previous years. Eosinophil counts were monitored at 3- to 6-month intervals. When counts became elevated, patients were enrolled in the study. Interleukin (IL)-4, IL-10, IL-12, transforming growth factor (TGF)-,, and interferon-, production by myelin basic protein,specific peripheral blood mononuclear cells were studied using enzyme-linked immunospot (ELISPOT). FoxP3 and Smad7 expression were studied by reverse-transcriptase polymerase chain reaction. Results During a 4.6-year follow-up period, parasite-infected MS patients showed a significantly lower number of exacerbations, minimal variation in disability scores, as well as fewer magnetic resonance imaging changes when compared with uninfected MS patients. Furthermore, myelin basic protein,specific responses in peripheral blood showed a significant increase in IL-10 and TGF-, and a decrease in IL-12 and interferon-,,secreting cells in infected MS patients compared with noninfected patients. Myelin basic protein,specific T cells cloned from infected subjects were characterized by the absence of IL-2 and IL-4 production, but high IL-10 and/or TGF-, secretion, showing a cytokine profile similar to the T-cell subsets Tr1 and Th3. Moreover, cloning frequency of CD4+CD25+ FoxP3+ T cells was substantially increased in infected patients compared with uninfected MS subjects. Finally, Smad7 messenger RNA was not detected in T cells from infected MS patients secreting TGF-,. Interpretation Increased production of IL-10 and TGF-,, together with induction of CD25+CD4+ FoxP3+ T cells, suggests that regulatory T cells induced during parasite infections can alter the course of MS. Ann Neurol 2007 [source] Reduced CD4+,CD25, T cell sensitivity to the suppressive function of CD4+,CD25high,CD127,/low regulatory T cells in patients with active systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 7 2008Ram Kumar Chowdary Venigalla Objective CD4+,CD25high regulatory T (Treg) cells play a crucial role in the maintenance of self tolerance and prevention of organ-specific autoimmunity. The presence of many in vivo,preactivated CD4+,CD25++ T cells in patients with systemic lupus erythematosus (SLE) poses a difficulty in discriminating CD25++ activated T cells from CD25high Treg cells. To overcome this problem, we analyzed the phenotype and function of CD4+,CD25high,CD127,/low natural Treg (nTreg) cells isolated from the peripheral blood of patients with SLE. Methods CD4+,CD25high,CD127,/low nTreg cells and CD4+,CD25, responder T (Tresp) cells from patients with SLE and normal donors were separated by fluorescence-activated cell sorting. Cell proliferation was quantified by 3H-thymidine incorporation, and immunophenotyping of the cells was done using FACScan. Results Comparable percentages of CD4+,CD25high,FoxP3+ T cells were observed in patients with SLE and normal donors. Proliferation of SLE nTreg cells sorted into the subset CD4+,CD25high,CD127,/low was significantly decreased compared with that of SLE nTreg cells sorted into the subset CD4+,CD25high (mean ± SEM 2,223 ± 351 counts per minute versus 9,104 ± 1,720 cpm, respectively), while in normal donors, these values were 802 ± 177 cpm and 2,028 ± 548 cpm, respectively, confirming that effector cell contamination was reduced. Notably, the suppressive activity of nTreg cells was intact in all groups. However, CD4+,CD25, Tresp cells isolated from patients with active SLE were significantly less sensitive than those from patients with inactive SLE to the suppressive function of autologous or normal donor CD4+,CD25high,CD127,/low nTreg cells. Furthermore, a significant inverse correlation was observed between the extent of T cell regulation in suppressor assays and the level of lupus disease activity. Conclusion This study is the first to show that, in human SLE, impaired sensitivity of Tresp cells to the suppressive effects of a comparably functional, highly purified nTreg cell population leads to a defective suppression of T cell proliferation in active SLE. Studies aiming to define the mechanisms leading to Tresp cell resistance might help in the development of highly specific, alternative immunotherapeutic tools for the control of systemic autoimmune diseases such as SLE. [source] T cell-mediated immunoregulation in the gastrointestinal tractALLERGY, Issue 4 2009L. Saurer In the intestinal tract, only a single layer of epithelial cells separates innate and adaptive immune effector cells from a vast amount of antigens. Here, the immune system faces a considerable challenge in tolerating commensal flora and dietary antigens while preventing the dissemination of potential pathogens. Failure to tightly control immune reactions may result in detrimental inflammation. In this respect, ,conventional' regulatory CD4+ T cells, including naturally occurring and adaptive CD4+ CD25+ Foxp3+ T cells, Th3 and Tr1 cells, have recently been the focus of considerable attention. However, regulatory mechanisms in the intestinal mucosa are highly complex, including adaptations of nonhaematopoietic cells and innate immune cells as well as the presence of unconventional T cells with regulatory properties such as resident TCR,, or TCR,, CD8+ intraepithelial lymphocytes. This review aims to summarize the currently available knowledge on conventional and unconventional regulatory T cell subsets (Tregs), with special emphasis on clinical data and the potential role or malfunctioning of Tregs in four major human gastrointestinal diseases, i.e. inflammatory bowel diseases, coeliac disease, food allergy and colorectal cancer. We conclude that the clinical data confirms some but not all of the findings derived from experimental animal models. [source] Role of ocular pigment epithelial cells in regional ocular immunityACTA OPHTHALMOLOGICA, Issue 2008S SUGITA Purpose To whether soluble factors by retinal pigment epithelial cells (RPE) promote the generation of T regulatory cells in vitro. Methods Primary cultured RPE cells were established from normal C57BL/6 mice. T cells were co-cultured with RPE, x-irradiated, and used as regulators (RPE Treg cells). Target bystander T cells were established from normal splenic T cells with anti-CD3 antibodies. T-cell activation was assessed for proliferation by [3H],thymidine incorporation. Expression of cytotoxic T lymphocyte antigen-2, (CTLA-2,) and cathepsin L on RPE and T cells was evaluated with oligonucleotide microarray, RT-PCR, immune staining, western blots and flow cytometry. Recombinant mouse CTLA-2, and anti-mouse CTLA-2, abs were used for the assay. For induction of experimental autoimmune uveitis (EAU), mice were immunized with interphotoreceptor retinoid-binding protein peptide emulsified in complete Freund's adjuvant. Results RPE converted CD4+ T cells into Treg cells by producing and secreting CTLA-2,, a cathepsin L inhibitor. CTLA-2, secreted by RPE cells selectively inhibited cathepsin L in the T cells and the cathepsin L-lacking T cells exhibited Treg phenotype, i.e. expression of Foxp3 and production of transforming growth factor beta (TGF,). CTLA-2, enhanced their production of active forms of TGF,. In addition, CD4+ T cells from EAU-induced cathepsin L knockout (KO) donors contained high population of Foxp3+ T cells and EAU in cathepsin L KO mice was significantly less than those in wild type mice. Furthermore, treatment with recombinant CTLA-2, significantly suppressed EAU. Conclusion These results indicate that immunosuppressive factors derived from RPE participate in the establishment of immune regulation in the posterior segment of the eye. [source] | ||||||||||