Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Induction of a chronic eczema is a most efficient therapy for alopecia areata (AA). We had noted a reduction in regulatory T cells during AA induction and wondered whether regulatory T cells may become recruited or expanded during repeated skin sensitization or whether additional regulatory cells account for hair regrowth. AA could not be cured by the transfer of CD4(+)CD25(high) lymph node cells from mice repeatedly treated with a contact sensitizer. This obviously is a consequence of a dominance of freshly activated cells as compared with regulatory CD4(+)CD25(+) T cells. Instead, a population of Gr-1(+)CD11b(+) cells was significantly increased in skin and spleen of AA mice repeatedly treated with a contact sensitizer. Gr-1(+)CD11b(+) spleen cells mostly expressed CD31. Expression of several proinflammatory cytokines as well as of the IFN-gamma receptor and the TNF receptor I were increased. Particularly in the skin, Gr-1(+) cells expressed several chemokines and CCR8 at high levels. Gr-1(+)CD11b(+) cells most potently suppressed AA effector cell proliferation in vitro and promoted partial hair regrowth in vivo. When cocultured with CD4(+) or CD8(+) cells from AA mice, the Gr-1(+)CD11b(+) cells secreted high levels of NO. However, possibly due to high level Bcl-2 protein expression in AA T cells, apoptosis induction remained unaltered. Instead, zeta-chain expression was strongly down-regulated, which was accompanied by a decrease in ZAP70 and ERK1/2 phosphorylation. Thus, a chronic eczema supports the expansion and activation of myeloid suppressor cells that, via zeta-chain down-regulation, contribute to autoreactive T cell silencing in vitro and in vivo.
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PMID:The importance of myeloid-derived suppressor cells in the regulation of autoimmune effector cells by a chronic contact eczema. 1791 92

The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 microg of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bcl-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8(+) cells, IL-10, or TGF-beta. In contrast, depletion of CD25(+) cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4(+)CD25(high) T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3(+)CD4(+)CD25(+) regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis.
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PMID:Hydrodynamic vaccination with DNA encoding an immunologically privileged retinal antigen protects from autoimmunity through induction of regulatory T cells. 1791

B-cell chronic lymphocytic leukemia (B-CLL) is a well-defined clinical entity with heterogeneous molecular and cytogenetic features. Here, we analyze the impact of trisomy 12, del(13q), del(17p), and del(11q) as determined by interphase fluorescence in situ hybridization analysis of purified neoplastic B-CLL cells on their immunophenotype, DNA ploidy status and proliferative rate.Overall, 111 of 180 (62%) B-CLL cases studied displayed one (50%) or more (12%) genetic abnormalities, del(13q) (35%) being more frequently detected than trisomy 12 (23%) followed by del(11q) (9%) and del(17p) (8%). Trisomy 12 was associated with a higher frequency of DNA aneuploidy, stronger expression of CD19, CD20, CD22, CD24, CD27, CD79b, CD38, and sIg and lower reactivity for CD43 with respect to cytogenetically nonaltered cases. In turn, cases with del(13q) displayed greater reactivity for CD20, FMC7, CD27, CD22, CD5, and bcl2, while del(11q) was associated with brighter expression of CD38, FMC7, CD25, and sIg. Hierarchical clustering analysis of the immunophenotype of B-CLL cases with cytogenetic abnormalities allowed the identification of three different groups of patients with increasing frequencies of trisomy 12, del(11q), and del(13q). Remarkably, none of the cytogenetic abnormalities analyzed except coexistence of 13q- and 17p- had a clear impact on the proliferative index of B-CLL cells.
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PMID:Impact of trisomy 12, del(13q), del(17p), and del(11q) on the immunophenotype, DNA ploidy status, and proliferative rate of leukemic B-cells in chronic lymphocytic leukemia. 1806 51

CD4+CD25+Foxp3+ regulatory T (Treg) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that Treg cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of Treg cells in Bim-/- and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25+ cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in Treg cells. Our study reveals that the survival of Treg cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate Treg homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate Treg cells that could be utilized for their therapeutic applications.
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PMID:The control of CD4+CD25+Foxp3+ regulatory T cell survival. 1830 52

The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.
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PMID:Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. 1895 59

We have previously demonstrated that multiple immunizations with vector-based vaccines containing transgenes for tumor Ags and a triad of costimulatory molecules (TRICOM) enhance the expansion and functional avidity of Ag-specific memory CD8(+) T cells in a mouse model. However, the effect of enhanced costimulation on human memory CD8(+) T cells is still unclear. The study reported here was an in vitro investigation of the proliferation and function of CEA-specific human memory CD8(+) T cells following enhanced costimulation. Our results demonstrated that TRICOM costimulation enhanced production of multiple cytokines and expansion of CEA-specific memory CD8(+) T cells. The lytic capacity of memory CTLs toward CEA(+) tumors was also significantly enhanced. IL-2R alpha (CD25) was upregulated dramatically following APC-TRICOM stimulation, suggesting that the enhanced expansion of memory CD8(+) T cells may be mediated by increased expression of IL-2R on memory T cells. The enhanced cytokine production and proliferation following TRICOM signaling was completely blocked by the combination of neutralizing Abs against B7-1, ICAM-1, and LFA-3, the costimulatory molecules comprising TRICOM. No difference in T-cell apoptosis was observed between APC-TRICOM and APC-wild-type groups, as determined by annexin V, Bcl-2, and active caspase-3 staining. Results indicated that enhanced costimulation greatly expanded human CEA-specific CD8(+) T cells and enhanced T-cell function, without inducing increased apoptosis of CEA-specific memory CD8(+) T cells.
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PMID:Antigen-presenting cells containing multiple costimulatory molecules promote activation and expansion of human antigen-specific memory CD8+ T cells. 1869 Apr 38

Previous studies have shown that treatment of ovariectomized females with 17-beta estradiol (E2) accelerates the development of autoimmunity in the (NZBxNZW)F(1) murine lupus model. Treatment with estrogenic organochlorine pesticides (OCPs) such as chlordecone produces a similar effect. Although it is reasonable to postulate that the effects of chlordecone and related OCPs on autoimmunity are due to their estrogenic effects, this has not been clearly demonstrated. The objective of this study was to compare effects of chlordecone and E2 on splenic T lymphocyte parameters plausibly related to autoimmunity; specifically, on T-cell phenotype and functions. Ovariectomized (NZBxNZW)F(1) mice were treated for 6 weeks with implanted sustained-release pellets containing chlordecone or E2 at dosing rates shown previously to significantly shorten time to onset of disease. E2, but not chlordecone, increased the percentage of activated and memory CD4 T-cells, and reduced naive CD4 T-cells. E2 also elevated CD25 and glucocorticoid-induced TNF receptor (GITR) levels in CD4 T-cells, an effect not shared by chlordecone. On the other hand, both chlordecone and E2 increased Bcl-2 expression in CD4 T-cells and reduced CD4 T-cell apoptosis without affecting their proliferation. Although both treatments increased TNF-alpha and IL-2 secretion by CD4 T-cells, only chlordecone increased secretion of IFN-gamma and GM-CSF. E2, but not chlordecone, increased IL-10 secretion. These observations indicate that although it is considered an estrogenic OCP, chlordecone exerts effects on splenic T-cells that are different in a number of ways from E2.
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PMID:Comparison of chlordecone and estradiol effects on splenic T-cells in (NZBxNZW)F(1) mice. 1895 62

Alterations in genes encoding transforming growth factor-beta-signaling components contribute to colon cancer in humans. Similarly, mice deficient in the transforming growth factor-beta signaling molecule, Smad3, develop colon cancer, but only after a bacterial trigger occurs, resulting in chronic inflammation. To determine whether Smad3-null lymphocytes contribute to increased cancer susceptibility, we crossed Smad3-null mice with mice deficient in both B and T lymphocytes (Rag2(-/-) mice). Helicobacter-infected Smad3/Rag2-double knockout (DKO) mice had more diffuse inflammation and increased incidence of adenocarcinoma compared with Helicobacter-infected Smad3(-/-) or Rag2(-/-) mice alone. Adoptive transfer of WT CD4(+)CD25(+) T-regulatory cells provided significant protection of Smad3/Rag2-DKO from bacterial-induced typhlocolitis, dysplasia, and tumor development, whereas Smad3(-/-) T-regulatory cells provided no protection. Immunohistochemistry, real-time reverse transcriptase-polymerase chain reaction, and Western blot analyses of colonic tissues from Smad3/Rag2-DKO mice 1 week after Helicobacter infection revealed an influx of macrophages, enhanced nuclear factor-kappaB activation, increased Bcl(XL)/Bcl-2 expression, increased c-Myc expression, accentuated epithelial cell proliferation, and up-regulated IFN-gamma, IL-1alpha, TNF-alpha, IL-1beta, and IL-6 transcription levels. These results suggest that the loss of Smad3 increases susceptibility to colon cancer by at least two mechanisms: deficient T-regulatory cell function, which leads to excessive inflammation after a bacterial trigger; and increased expression of proinflammatory cytokines, enhanced nuclear factor-kappaB activation, and increased expression of both pro-oncogenic and anti-apoptotic proteins that result in increased cell proliferation/survival of epithelial cells in colonic tissues.
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PMID:Bacterial infection of Smad3/Rag2 double-null mice with transforming growth factor-beta dysregulation as a model for studying inflammation-associated colon cancer. 1911 84

Human neural stem cells (hNSCs) can control inflammation in the central nervous system, although the underlying mechanisms are not understood fully. We investigated the immunomodulatory effect of hNSCs on human T cells and the underlying mechanisms. Culture supernatant from an immortalized hNSC cell line, HB1.F3, which has a therapeutic effect on acute stroke and intracerebral hemorrhage, suppressed the proliferation of allogeneically or mitogenically stimulated human peripheral T cells, including the CD3(+)CD103(+) subpopulation. CFSE labeling and flow cytometry showed that the suppression of proliferation was caused by cell cycle arrest and induction of apoptosis. The lack of significant change in caspase-8 levels and the significant reduction in Bcl-2 expression in the affected T cells suggest that the intrinsic pathway plays a major role in soluble-factor-mediated T-cell apoptosis. The addition of culture supernatant from hNSCs to activated T cells reduced the expression of the activation markers CD69 and CD25 at 24 hr after activation, but at 48 hr only CD69 was down-regulated. A cytometry bead assay showed that the secretion of interleukin (IL)-2 decreased significantly, whereas that of IL-4, IL-10, tumor necrosis factor-alpha, and interferon-gamma increased. These results show that hNSCs can negatively affect human peripheral T cells by suppressing their activation and proliferation through soluble mediators, suggesting that hNSCs have a bystander immunomodulatory effect on T cells.
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PMID:Soluble mediators from human neural stem cells play a critical role in suppression of T-cell activation and proliferation. 1930 23

Two subsets of natural and adaptive regulatory T (T reg) cells have been described, but the identity of adaptive type 1 regulatory (Tr1)-like cells in humans is unclear. We analyzed a subset of human blood CD4(+) T cells--CD45RA(-)CD25(-)interleukin (IL)-7 receptor (R)(-) cells--that rapidly secreted high levels of IL-10 together with interferon gamma, but produced little IL-2. These IL-7R(-) T cells were rare, anergic, and largely Foxp3(-). They expressed low levels of Bcl-2 but high levels of Ki-67 and ICOS, suggesting that they have been recently activated in vivo. Consistently, they responded selectively to persistent foreign and self-antigens under steady-state conditions. Unlike natural CD25(+) T reg cells, IL-7R(-) cells suppressed naive and memory T cell proliferation in an IL-10-dependent fashion, and they required strong T cell receptor stimulation for suppression. To our knowledge, this is the first report that identifies Tr1-like cells in human blood. These IL-10-secreting cells have characteristics of chronically activated Th1 effector cells and are distinct from CD25(+) T reg cells.
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PMID:Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood. 1941 53


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