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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. Administration of interleukin 12 (IL-12), a key cytokine which guides the development of T helper type 1 (Th1) CD4+ T cells, induces rapid onset of IDDM in NOD, but not in BALB/c mice. Histologically, IL-12 administration induces massive infiltration of lymphoid cells, mostly T cells, in the pancreatic islets of NOD mice. CD4+ pancreas-infiltrating T cells, after activation by insolubilized anti T cell receptor antibody, secrete high levels of interferon gamma and low levels of IL-4. Therefore, IL-12 administration accelerates IDDM development in genetically susceptible NOD mice, and this correlates with increased Th1 cytokine production by islet-infiltrating cells. These results hold implications for the pathogenesis, and possibly for the therapy of IDDM and of other Th1 cell-mediated autoimmune diseases.
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PMID:Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. 783 34

We performed limiting dilution culture of T cells from a patient affected by primary immunodeficiency as a result of complete lack of adenosine deaminase (ADA) activity and also affected by insulin-dependent diabetes mellitus (type I diabetes). Despite the occurrence of immunodeficiency, we were able to raise and grow T cell clones derived from this patient in long-term culture. These T cells displayed ADA enzymatic activity and produced interleukin-2 after engagement of their T cell receptor (TCR)/CD3 complex. We analyzed the TCR repertoire of such clones by nucleotide sequencing of TCR beta chains. The results show that the T cell clones express different V beta but similar J regions. However, the CDR3 regions which are implicated in antigen recognition were found to be heterogeneous.
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PMID:Long-term culture and T cell receptor analysis of T cell clones isolated from a patient with adenosine deaminase deficiency and type I diabetes. 795 66

The frequencies of Bgl 11 and BamH1 restriction fragment length polymorphisms (RFLP) of C beta, V beta 8, V beta 11 and V beta 7.2 have been defined in a healthy Australian population. Linkage disequilibrium between alleles of the T cell receptor (TCR) V beta 8 and V beta 11 gene segments has been confirmed. We have also confirmed the lack of linkage disequilibrium between either of these loci and alleles at C beta or V beta 7.2. Using RFLPs at V beta 11 and V beta 8 loci TCR beta haplotypes have been identified in five families in which the probands have insulin-dependent diabetes mellitus (IDDM). An extremely rare haplotype, marked by the higher molecular weight BamH1 allele (H, H) at each of V beta 11 and V beta 8, was found in the DR4+ DR3- probands of two families (P = 0.004). In three families in which the probands had DR3, the more common TCR haplotype LH (V beta 11, V beta 8) was found. Taken together, these data confirm that linkage disequilibrium does exist in the TCR beta locus, at least in some regions, and suggest that detailed analysis of the relationship between TCR V beta haplotypes and HLA is warranted since these RFLPs may be markers for important allelic V gene sequence variations.
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PMID:T cell receptor haplotypes in families of patients with insulin-dependent diabetes mellitus. 809 39

Diabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal gamma irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4+ and CD8+ T cells and macrophages. The CD8+ T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4+ T cell subset, isolated from healthy syngeneic donors, of the phenotype CD45RClow T cell receptor alpha/beta+ RT6+ Thy-1- OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (IL-2) and IL-4, but no interferon gamma, on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells.
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PMID:Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. 809 34

Non-obese diabetic (NOD) mice become spontaneously diabetic as a result of a genetically programmed autoimmune process mediated by autoreactive T lymphocytes and directed against beta cell antigen(s). Studies dealing with T cell receptor (TcR) variable (V) gene usage by such autoreactive T lymphocytes have given contrasted results. Various reasons may explain these discrepancies: the multiplicity of antigenic epitopes putatively recognized by T cells, the ambiguity between specifically committed T cells and passenger lymphocytes homing randomly to the pancreas, the necessarily limited size of the T cell clone panels which have been analyzed for TcR rearrangements and, last but not least, the flexibility of T cell repertoires. To circumvent some of these difficulties, we have decided to concentrate upon the T cell population present in diseased animals and capable of transferring diabetes into young naive NOD recipients. This population, composed of CD4+ and CD8+ T cells, is presumably committed against the relevant beta cell antigens and is the most likely to reveal a bias in V gene usage if such a bias does indeed exist. To find out whether certain V beta genes are more frequently used than others by such pathogenic T cells, T lymphocytes from diabetic donors have been depleted in vitro of defined V beta subsets before being reinoculated into permissive recipients. Out of four V beta families probed under such conditions, three (V beta 8, V beta 5 and V beta 11) are neutral. Their absence neither increases nor reduces the final incidence of successful transfers, indicating that these gene segments are not preferentially used. In contrast, the depletion of V beta 6-positive T cells results in a severe reduction of transfers, suggesting that V beta 6 gene is used with a relatively high frequency by diabetogenic CD4+ and/or CD8+ T cells. To define more precisely which subset uses V beta 6 gene preferentially, we have performed mixing experiments with deleted and intact subsets. The results, based on disease transfer and insulitis severity, indicate that the V beta 6 bias affects predominantly the CD4+ subset. Thus, at variance with several studies concluding that V gene usage in NOD mice is heterogeneous, our present data suggest that disease transferring T cells use a relatively restricted set of V beta genes.
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PMID:Evidence for a preferential V beta usage by the T cells which adoptively transfer diabetes in NOD mice. 809 59

The autoimmune process leading to the destruction of pancreatic beta-cells is mediated by T lymphocytes. Peripheral T cells from subjects with preclinical and clinical type I diabetes respond weakly in vitro to lectin stimulation. We, therefore, investigated in a group of newly diagnosed diabetic patients the presence of a defect in the signal transduction pathway of the T cell receptor (TcR)/CD3 complex. Following stimulation with anti-CD3-coupled beads, the proliferative response in diabetic T cells was significantly decreased in comparison with that from normal T cells. Interestingly, addition of either recombinant interleukin (IL)-2 or phorbol 12-myristate 13-acetate to the cell culture was able to completely restore impaired anti-CD3-induced proliferation in diabetic T cells, suggesting the presence of a defect through the TcR/CD3 pathway, located upstream of protein kinase C (PKC) activation and resulting in low IL-2 production and proliferation. Intracellular Ca2+ measurements by Fluo-3 labeling and flow cytometry analysis on diabetic and control T cells after anti-CD3 stimulation gave comparable results, indicating that this defect does not involve events leading to intracellular Ca2+ mobilization. In contrast, anti-CD3 stimulation of diabetic T cells resulted in a marked impairment of PKC translocation and CD69 antigen expression, as assessed by peptide substrate phosphorylation and by flow cytometry analysis, respectively. Taken together, our data clearly show the presence in individuals at the onset of the disease of an in vitro defect in the signal transduction pathway of the TcR/CD3 complex, resulting in ineffective PKC activation which is not able to induce normal IL-2 production and proliferation of diabetic T cells.
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PMID:Defective T cell receptor/CD3 complex signaling in human type I diabetes. 814 68

Strategies for studying the genetics of autoimmune diseases have undergone a considerable evolution during the last years, especially due to molecular biology techniques and to systematic genome studies. Genetic factors account for 20 to 40% of the risk, and environmental elements play a major role. The major histocompatibility complex comprising HLA genes remains the immunogenetic system most studied and most closely associated with various autoimmune diseases. These associations are mainly observed with HLA class II genes polymorphisms; the precise knowledge of their structure has allowed to define HLA sequence polymorphisms which are themselves risk markers: specific combinations of HLA-DQA and DQB alleles in insulin-dependent diabetes mellitus or a given DR, DQ haplotype for multiple sclerosis. No strong association with HLA-DP has been demonstrated. In all cases the genes involved have a normal structure and the disease is secondary to the combination of a given set of genes with environmental factors. The present knowledge of insulin-dependent diabetes mellitus and multiple sclerosis genetics is rather advanced. Other genes of the HLA region might also be involved in the genetic susceptibility. Results about other immunogenetic systems (T cell receptor genes or heavy chain immunoglobulin genes) are still contradictory but no major gene for autoimmune susceptibility seems to exist in these regions; however autoimmune diseases are under polygenic control; susceptibility genes shared between different diseases often occurring within the same families (Graves' disease and insulin-dependent diabetes mellitus) and genes specific for a given disease (insulin gene region in diabetes) both exist. The present rapid progress in this area is due to the use of highly polymorphic markers randomly distributed across the genome (microsatellites being most informative) and that of animal models: the list of "candidate genes or regions" potentially involved in the genetics of autoimmune diseases is enlarging; the development of coordinated epidemiological studies of molecular genetics along with the sharing of biological resources between different teams allow to build up powerful informative studies which will confirm or refute those "candidates". However, once the list of genes involved is established their mechanism of action will still take time to elucidate.
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PMID:[Genetics of autoimmune diseases]. 817 58

The T cell receptor (TCR) requirements in the pathogenesis of insulin-dependent diabetes were examined with transgenic NOD mice bearing nondisease-related TCR alpha and beta chains. In both TCR beta and TCR alpha beta transgenic NOD mice the beta chain transgene was expressed by > 98% of peripheral T cells. The alpha chain transgene was also highly expressed. Insulitis developed in both sets of transgenic animals with most of the lymphocytes in the lesion expressing the transgenic beta chain and with depletion of the endogenous TCR V beta genes. Nonetheless, NOD animals transgenic for TCR beta and TCR alpha beta developed diabetes similar to controls. Thus, skewing the TCR repertoire did not diminish autoimmune susceptibility in NOD mice.
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PMID:Progression to diabetes in nonobese diabetic (NOD) mice with transgenic T cell receptors. 826 84

Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism responsible for NOD thymic T cell proliferative unresponsiveness and determining whether reversal of this unresponsiveness protects NOD mice from diabetes. Interleukin 4 (IL-4) secretion by thymocytes from > 7-wk-old NOD mice was virtually undetectable after treatment with either anti-TCR alpha/beta, anti-CD3, or Concanavalin A (Con A) compared with those by thymocytes from age- and sex-matched control BALB/c mice stimulated under identical conditions. NOD thymocytes stimulated by anti-TCR alpha/beta or anti-CD3 secreted less IL-2 than did similarly activated BALB/c thymocytes. However, since equivalent levels of IL-3 were secreted by Con A-activated NOD and BALB/c thymocytes, the unresponsiveness of NOD thymic T cells does not appear to be dependent on reduced IL-2 secretion. The surface density and dissociation constant of the high affinity IL-2 receptor of Con A-activated thymocytes from both strains are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3-activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogenous IL-4 reverses the unresponsiveness of both NOD thymic and peripheral T cells completely, and this is associated with the complete restoration of an IL-2 secretion response. Furthermore, the in vivo administration of rIL-4 to prediabetic NOD mice protects them from diabetes. Thus, the ability of rIL-4 to reverse completely the NOD thymic and peripheral T cell proliferative defect in vitro and protect against diabetes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diabetes in NOD mice.
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PMID:Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. 831 97

In most cases, insulin-dependent diabetes results from autoimmune elimination of pancreatic beta cells by T lymphocytes that are generated as a result of complex polygenic interactions between particular MHC haplotypes and non-MHC linked susceptibility modifiers. Immature T cells with potential autoreactivity are normally destroyed in the thymus when they are highly activated after ligation of the T cell receptor (TCR) with "self" peptides bound to MHC molecules on antigen presenting cells (APC) such as macrophages. Here the hypothesis is put forth that non-MHC linked diabetes susceptibility genes contribute to subtle defects in the maturation of macrophages, and in synergy with a diabetogenic MHC haplotype generate APC that are unable to trigger autoreactive T cells to an activation state high enough to induce their destruction.
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PMID:Autoimmune diabetes results from genetic defects manifest by antigen presenting cells. 837 Apr 80


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