Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4(+)CD25(+) T-cells can be used to interfere with spontaneous autoimmune diseases such as type 1 diabetes. However, their low frequency and often unknown specificity represent major obstacles to their therapeutic use. Here we have explored the fact that ectopic expression of the transcription factor Foxp3 can confer a suppressor phenotype to naive CD4(+) T-cells. We found that retroviral transduction of polyclonal CD4 T-cells with FoxP3 was not effective in interfering with established type 1 diabetes. Thus, more subtle and more organ-specific regulation might be required to prevent type 1 diabetes, as well as to avoid systemic immunosuppression. However, a single injection of 10(5) FoxP3-transduced T-cells with specificity for islet antigen stabilized and reversed disease in mice with recent-onset diabetes. By comparing FoxP3-transduced T-cells with various antigen specificities, it became clear that the in vivo effect correlated with specific homing to and activation in pancreatic lymph nodes and not with in vitro suppressor activity or cytokine production. Our results complement recent results on in vitro-amplified antigen-specific T-cells in ameliorating type 1 diabetes and suggest that FoxP3 transduction of expanded T-cells might achieve the same goal.
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PMID:Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. 1559 38

Accumulating evidence that granulocyte colony-stimulating factor (G-CSF), the key hematopoietic growth factor of the myeloid lineage, not only represents a major component of the endogenous response to infections, but also affects adaptive immune responses, prompted us to investigate the therapeutic potential of G-CSF in autoimmune type 1 diabetes. Treatment with G-CSF protected NOD mice from developing spontaneous diabetes. G-CSF triggered marked recruitment of dendritic cells (DCs), particularly immature CD11c(lo)B220(+) plasmacytoid DCs, with reduced costimulatory signal expression and higher interferon-alpha but lower interleukin-12p70 release capacity than DCs in excipient-treated mice. G-CSF recipients further displayed accumulation of functional CD4(+)CD25(+) regulatory T-cells that produce transforming growth factor-beta1 (TGF-beta1) and actively suppressed diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. G-CSF's ability to promote key tolerogenic interactions between DCs and regulatory T-cells was demonstrated by enhanced recruitment of TGF-beta1-expressing CD4(+)CD25(+) cells after adoptive transfer of DCs isolated from G-CSF- relative to vehicle-treated mice into naive NOD recipients. The present results suggest that G-CSF, a promoter of tolerogenic DCs, may be evaluated for the treatment of human type 1 diabetes, possibly in association with direct inhibitors of T-cell activation. They also provide a rationale for a protective role of the endogenous G-CSF produced during infections in early diabetes.
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PMID:Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4(+)CD25(+) regulatory T-cells. 1561 13

Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to self-antigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4(+)CD25(+) T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4(+)CD25(+) Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4(+)CD25(+) T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P = 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-gamma (P = 0.005) and decreased interleukin-10 production (P = 0.03). These deficiencies may reflect a disturbance in the balance of the CD4(+)CD25(+) population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P = 0.007) and intracellular CTLA-4 (P = 0.01). These data demonstrate deficiency in function of the CD4(+)CD25(+) Treg population that may influence the pathogenesis of type 1 diabetes.
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PMID:Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. 1561 15

Little is known about the pathogenic role of B cell dysfunction in T cell-mediated autoimmune disease. We previously reported that B cell hyper-responsiveness, resistance to apoptosis, and accumulation in islets occur during the onset of insulitis, but not in type 1 diabetes (T1D), in NOD mice. In this study we extended these studies to further determine how islet-infiltrated B cells contribute to this inflammatory insulitis. We demonstrate the presence of an increased percentage of B7-1(+) and a decreased percentage of B7-2(+) B cells in the spleen of autoimmune disease-prone NOD and nonobese diabetes-resistant mice compared with the spleen of nonautoimmune disease-prone C57BL/6 and BALB/c mice. An age-dependent differential expression of B7-1 and B7-2 was associated with the development of insulitis and CD4(+)CD25(+) T cell deficiency in autoimmune disease-prone mice. Whereas BCR and LPS stimulation increased B7-2 expression on B cells from autoimmune disease-prone and nonautoimmune disease-prone mice, LPS-induced B7-1 expression was higher on NOD than C57BL/6 B cells. Interestingly, increased expression of B7-1 and B7-2 was found on islet-infiltrated B cells, and this increase was associated with enhanced T cell costimulation. Islet-infiltrated B cells were shown to be a source of TNF-alpha production in islets. B7 blockade of BCR-stimulated NOD B cells by anti-B7-1 and anti-B7-2 mAbs during coadoptive transfer with diabetogenic T cells into NOD.scid mice protected these recipients from T1D. These results suggest that increased B7-1 and B7-2 expression on islet-infiltrated NOD B cells is associated with increased T cell costimulation and the development of inflammatory insulitis in NOD mice.
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PMID:Dysregulated B7-1 and B7-2 expression on nonobese diabetic mouse B cells is associated with increased T cell costimulation and the development of insulitis. 1563 86

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.
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PMID:Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. 1577 95

Although T-cell clones bearing T-cell receptors with high affinity for self-peptide major histocompatibility complex (MHC) products are generally eliminated in the thymus (recessive tolerance), the peripheral T-cell repertoire remains strongly biased toward self-peptide MHC complexes and includes autoreactive T cells. A search for peripheral T cells that might exert dominant inhibitory effects on autoreactivity has implicated a subpopulation of CD4(+)CD25(+) T cells called regulatory T cells (Tregs). Here, we discuss the role of cytokines and costimulatory molecules in the generation, maintenance, and function of Tregs. We also summarize evidence for the involvement of Tregs in controlling autoimmune diseases, including type 1 diabetes, experimental autoimmune encephalomyelitis, and inflammatory bowel disease. Last, we discuss our recent definition of the potential role of B7 expressed on activated T-effector cells as a target molecule for Treg-dependent suppression. These observations suggest that the engagement of B7 on effector T cells transmits an inhibitory signal that blocks or attenuates effector T-cell function. We restrict our comments to the suppression mediated by cells within the CD4 lineage; the impact of the cells within the CD8 lineage that may suppress via engagement of Qa-1 on effector T cells is not addressed in this review.
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PMID:Regulatory T cells and autoimmune disease. 1579 Mar 60

Natural CD4(+)CD25(+) regulatory T (CD4(+)CD25(+) T reg) cells play a key role in the immunoregulation of autoimmunity. However, little is known about the interactions between CD4(+)CD25(+) T reg cells and autoreactive T cells. This is due, in part, to the difficulty of using cell surface markers to identify CD4(+)CD25(+) T reg cells accurately. Using a novel real-time PCR assay, mRNA copy number of FoxP3, TGFbeta1, and interleukin (IL)-10 was measured in single cells to characterize and quantify CD4(+)CD25(+) T reg cells in the nonobese diabetic (NOD) mouse, a murine model for type 1 diabetes (T1D). The suppressor function of CD4(+)CD25(+)CD62L(hi) T cells, mediated by TGFbeta, declined in an age-dependent manner. This loss of function coincided with a temporal decrease in the percentage of FoxP3 and TGFbeta1 coexpressing T cells within pancreatic lymph node and islet infiltrating CD4(+)CD25(+)CD62L(hi) T cells, and was detected in female NOD mice but not in NOD male mice, or NOR or C57BL/6 female mice. These results demonstrate that the majority of FoxP3-positive CD4(+)CD25(+) T reg cells in NOD mice express TGFbeta1 but not IL-10, and that a defect in the maintenance and/or expansion of this pool of immunoregulatory effectors is associated with the progression of T1D.
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PMID:Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. 1583 17

CD4+ CD25+ T-cells appear to play a crucial role in regulating the immune response. Therefore, we evaluated the peripheral blood frequency and function of CD4+ CD25+ T-cells in 70 type 1 diabetic patients and 37 healthy individuals. Interestingly, a positive correlation was observed between increasing age and CD4+ CD25+ T-cell frequency in both subject groups. In contrast to previous studies of nonobese diabetic mice and type 1 diabetic patients, similar frequencies of CD4+ CD25+ and CD4+ CD25(+Bright) T-cells were observed in healthy control subjects and type 1 diabetic patients of similar age. There was no difference between type 1 diabetic subjects of recent-onset versus those with established disease in terms of their CD4+ CD25+ or CD4+ CD25(+Bright) T-cell frequency. However, type 1 diabetic patients were markedly defective in their ability to suppress the proliferation of autologous effector T-cells in vitro. This type 1 diabetes-associated defect in suppression was associated with reduced production of interleukin (IL)-2, gamma-interferon, and transforming growth factor-beta, whereas other cytokines including those of adaptive and innate immunity (IL-10, IL-1beta, IL-6, IL-8, IL-12p70, and tumor necrosis factor-alpha) were similar in control subjects and type 1 diabetic patients. These data suggest that age strongly influences the frequency of CD4+ CD25+ T-cells and that function, rather than frequency, may represent the means by which these cells associate with type 1 diabetes in humans.
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PMID:Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. 1585 27

The crucial role of regulatory cells in self-tolerance and autoimmunity has been clearly established in numerous types of regulatory cells, the majority of which are CD4(+) T cells. Much focus has been placed on thymically derived CD4(+)CD25(+) regulatory T cells, given that the depletion of this subset in murine models results in the spontaneous development of autoimmune diseases. These naturally occurring regulatory T cells are found to be functionally mature in the thymus, and exert suppression in a contact-dependent manner. Another important category of immunosuppressive cells consists of conditionally induced regulatory T cells such as Tr1, Th3, and various other CD4(+) lymphocytes. Understanding the development and regulatory functions of immunoregulatory cells may elucidate the etiology for loss of self-tolerance. This review will summarize the characteristics, developmental pathways, and functions of regulatory T cells, as well as their role in human autoimmune diseases including multiple sclerosis, rheumatoid arthritis, Myasthenia Gravis, Kawasaki disease, autoimmune polyglandular syndrome type II, type 1 diabetes, autoimmune lymphoproliferative syndrome, and systemic lupus erythematosus.
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PMID:Regulatory T cells: development, function and role in autoimmunity. 1608 Oct 26

Nonobese diabetic (NOD) mice serve as a model of spontaneous type 1 diabetes (T1D), a T cell-mediated autoimmune disease leading to the destruction of pancreatic insulin-producing beta islet cells. A possible deficiency in regulatory T (T(reg)) cell development or function may promote the activation, expansion, and recruitment of autoreactive T cells and the onset of T1D. Naturally occurring CD4(+)CD25(+) T(reg) (nT(reg)) cells, which typically display potent inhibitory effects on T cell functions in vitro and in vivo, may be defective at controlling autoimmunity in T1D. We have examined the relative contribution of CD4(+)CD25(+) nT(reg) cells in the immune regulation of T1D in the NOD mouse model. CD4(+)CD25(+) T cells represent 5-10% of CD4(+) thymocytes or peripheral T cells from prediabetic neonatal NOD mice, are anergic to TCR signals, and potently suppress activated T cells in a contact-dependent and cytokine-independent fashion in vitro. Unlike total CD4(+) T cells, prediabetic CD25(+)-depleted CD4(+) T cells are potently diabetogenic when transferred in immunodeficient NOD mice. Co-transfer of CD4(+)CD25(+) T cells from thymocytes or peripheral lymphoid tissues of neonatal NOD mice dramatically halts disease development and beta-islet cell lymphocytic infiltration, even when T1D is induced by CD4(+) T cells from BDC2.5 transgenic or diabetic NOD mice. Finally, we show that CD4(+)CD25(+) T(reg) preferentially accumulate in inflamed pancreatic environments, where they potently inhibit the antigen-specific expansion and cytokine effector functions of diabetogenic T cells. Thus, CD4(+)CD25(+) T cell-mediated regulation is operative in the prediabetic neonatal T cell repertoire and can suppress the diabetogenic process and control the onset of T1D.
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PMID:Control of type 1 autoimmune diabetes by naturally occurring CD4+CD25+ regulatory T lymphocytes in neonatal NOD mice. 1612 46


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