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

To address the mechanisms of tolerance to extrathymic proteins, we have generated transgenic mice expressing the lymphocytic choriomeningitis viral (LCMV) glycoprotein (GP) in the beta islet cells of the pancreas. The fate of LCMV GP-specific T cells was followed by breeding the GP transgenic mice with T cell receptor transgenic mice, specific for LCMV and H-2Db. These studies suggest that "peripheral tolerance" of self-reactive T cells does not involve clonal deletion, clonal anergy, or a decrease in the density of T cell receptors or accessory molecules. Instead, this model indicates that self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of appropriate T cell activation. Infection of transgenic mice with LCMV readily abolishes peripheral unresponsiveness to the self LCMV GP antigen, resulting in a CD8+ T cell-mediated diabetes. These data suggest that similar mechanisms may operate in several so-called "T cell-mediated autoimmune diseases."
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PMID:Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. 190 64

Allelic polymorphism in the T cell receptor constant beta-chain gene region has been reported to be associated with autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). The present analysis of 164 children and adolescents with IDDM and 193 controls for BqlII polymorphism using a TcR-C beta cDNA probe revealed two allelic restriction fragments with sizes of 10.5 kb (U) and 9.6 kb (L). No particular association was observed between the RFLP genotypes and IDDM (UU 27% versus 31%; UL 53% versus 52%; and LL 20% versus 17%, in diabetic subjects and controls, respectively), nor were any differences found between patients with various HLA risk antigens. The frequency of heterozygotes was 52% in 63 DR3-positive diabetic subjects and 53% in 73 DR3-negative ones. The results do not support any involvement of the TcR constant region genes in susceptibility to IDDM.
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PMID:Lack of association of T cell receptor beta-chain constant region polymorphism with insulin-dependent diabetes mellitus in Finland. 197 78

We have studied the BglII polymorphism near the T cell receptor beta chain constant region (TcR-C beta) gene, HLA-DR genotypes and certain autoimmune features in 102 patients with type I (insulin-dependent) diabetes. There was a significant decrease in the frequency of the 1:1 genotype (P = 0.008) and an increase in the 1:2 genotype (P = 0.03) of the BglII TcR polymorphism in the group of patients who developed type-I diabetes after the age of 20 years. This group of patients also showed an increased incidence of autoantibodies (especially islet cell antibody), a family history of diabetes and the presence of other autoimmune diseases. The frequency of this polymorphism in patients who developed type I diabetes before the age of 20 years was similar to a non-diabetic group. These results suggest that there are two genetically distinct groups of patients with type I diabetes. HLA-DR3 and HLA-DR4 genotypes were also increased in the diabetic patients but no significant difference was observed between HLA-DR genotypes, the TcR-C beta genotypes, the age of diagnosis or with other autoimmune features. Patients developing type I (insulin-dependent) diabetes after the age of 20 years have an additional genetic susceptibility for diabetes associated with the TcR-C beta gene.
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PMID:A T cell receptor beta chain polymorphism is associated with patients developing insulin-dependent diabetes after the age of 20 years. 197 39

Our aim was to derive T lymphocyte lines that specifically recognize islet antigens in murine models of autoimmune diabetes. Islets of Langerhans infiltrated with lymphocytes were isolated either from mice previously injected with multiple low doses of streptozotocin or from NOD-WEHI mice and were cultured in the presence of the T cell growth factor, interleukin 2 (IL-2). With islets from both models of autoimmune diabetes, rapidly proliferating, large granular lymphocytes emerged after 7-10 days and destroyed the islets and other cells such as fibroblasts in the cultures. Cytotoxicity assays showed that these cells were capable of destroying both P815 and YAC-1 tumor cells. In contrast to lymphocytes present initially in the islet infiltrates which express predominantly the L3T4 marker, the large granular lymphocytes were shown to be Ly-2 positive. They also expressed the alpha beta T cell receptor and contained mRNA for the alpha beta T cell receptor demonstrable by in situ hybridization. While morphologically similar to NK cells these large granular lymphocytes bear T cell markers and destroy a broader range of targets. They may represent a minor population of T lymphocytes particularly responsive to IL-2 although other studies show that T cells generally can develop a similar phenotype after prolonged culture with IL-2. The lack of target cell specificity indicates that these IL-2-stimulated large granular lymphocytes are unlikely to mediate the immunopathogenesis of diabetes in these animal models.
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PMID:Murine models of autoimmune diabetes: nonspecific cytotoxic lymphocytes derived from pancreatic islets in the presence of IL-2. 252 76

Autoimmunity is paradoxically a physiologic phenomenon. One finds in normal sera natural autoantibodies that are encoded by germ line genes. Autoimmunity is at the origin of common and severe diseases such as diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus and perhaps psoriasis and Crohn's disease. The disease may be due according to cases to exacerbation of physiologic autoimmunity or to appearance of autoreactive clones producing autoantibodies encoded by mutated genes. The respective role of triggering environmental factors and genetic predisposition (HLA and non HLA genes) is not determined. New immunotherapeutic methods, particularly cyclosporine, monoclonal antibodies (against T cells, CD4 and T cell receptor molecules and Ia antigens) and autoantigen-specific vaccination open new major therapeutic perspectives that presage major improvement in the prognosis of these diseases.
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PMID:[Evolution of the concept of autoimmunity and its therapeutic implications]. 267 84

Autoimmune (type 1) diabetes mellitus in mouse, rat, and humans shares several features, including T lymphocyte infiltration into pancreatic islets and a dependence on permissive class II major histocompatibility complex (MHC) alleles. We report here on an experimental model involving mice that express influenza hemagglutinin (HA) under the control of the insulin promoter and, at the same time, a transgenic class II MHC-restricted T cell receptor (TcR) specific for an HA peptide. These mice spontaneously develop islet infiltrates resembling those found in NOD mice and most animals become diabetic within 8 weeks of age. Because of the availability of a clonotypic TcR antibody, we can be confident that the Ins-HA transgene does not induce any measurable alterations in the vast majority of T cells with the transgenic TcR in primary and secondary lymphoid organs. Continuous export of large numbers of HA-specific lymphocytes from the thymus was not required for the manifestation of the disease since mice thymectomized at 3 days after birth still developed the disease albeit with smaller infiltrates.
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PMID:On the various manifestations of spontaneous autoimmune diabetes in rodent models. 752 72

To address the mechanisms of tolerance to extrathymic proteins, we have generated transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) in the beta islet cells of the pancreas. The fate of LCMV-GP-specific T cells was followed by breeding the GP transgenic mice with T cell receptor transgenic mice, specific for LCMV-GP and H-2Db. These studies suggest that "Peripheral tolerance" of self-reactive T cells does not involve clonal deletion, clonal anergy, or a decrease in the density of T cell receptors or accessory molecules. Instead, this model indicates that potentially self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of appropriate T cell activation. Infection of transgenic mice with LCMV readily abolishes peripheral unresponsiveness to the self LCMV-GP antigen, resulting in a CD8+ T cell-mediated diabetes. These data suggest that similar mechanisms may operate in several so called "T cell-mediated autoimmune diseases". A synthetic peptide corresponding to an immunodominant epitope of lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) was used to prime or to tolerize CD8+ T cells in vivo, dependent on the mode of immunization. Peptide-specific tolerance was then examined in transgenic mice expressing LCMV-GP in the beta islet cells of the pancreas; these mice develop CD8+ T cell-mediated diabetes within 8-14 days after LCMV infection. Specific peptide-induced tolerance prevented autoimmune destruction of beta islet cells and diabetes in this transgenic mouse model.
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PMID:[Viral antigen induced autoimmunity: an animal model for diabetes mellitus type I]. 753 82

Antigen-specific T cell activation requires two independent signalling events, one mediated through T cell receptor engagement by the antigen-presenting cell-expressed peptide/class II major histocompatibility complex, and the second through the cognate interactions of costimulatory molecules expressed on the T cell and antigen-presenting cell. There is evidence from in vitro and in vivo experimental systems suggesting that the CD28/B7 costimulatory pathway is crucial for induction of maximal T cell proliferation and T helper-B cell collaboration for IgG production. This pathway can be blocked by CTLA-4-Ig, a soluble form of CTLA-4 which binds with high avidity to the CD28 ligands, B7-1 and B7-2. Here, we show that CTLA-4-Ig treatment prevents clinical and histological manifestations of disease in a collagen-induced arthritis model of rheumatoid arthritis in the diabetes resistant BB/Wor rat, when therapy is initiated before immunization with bovine type II collagen (BIIC). Anti-BIIC antibody titers are reduced in CTLA-4-Ig-treated rats compared to diseased control animals. Histologically, joints from CTLA-4-Ig-treated animals show no histological abnormalities, in contrast to control antibody-treated animals, which show complete erosion of the articular cartilage and bone. Despite the efficacy of CTLA-4-Ig in preventing clinical and histological signs of arthritis and reducing antibody responses to BIIC, delayed type hypersensitivity responses to collagen 18 d or more after CTLA-4-Ig treatment ends are similar in CTLA-4-Ig-treated and untreated rats, suggesting that the prolonged disease suppression observed does not result from induction of T cell anergy.
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PMID:Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-4-Ig. 754 97

It has been proposed that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells: TH1 cells would promote diabetes, whereas TH2 cells would actually protect from disease. This proposition was tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice. TH1-like cells actively promoted diabetes; TH2-like cells invaded the islets but did not provoke disease--neither did they provide substantial protection.
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PMID:T helper cell subsets in insulin-dependent diabetes. 776 37

Among diabetes-susceptibility genes in NOD mice, only Idd-1 has been clearly assigned: Idd-1 could be a gene complex composed of class II major histocompatibility complex (MHC) genes, I-A beta and I-E. Employing restriction fragment length polymorphism (RFLP) analysis and nucleotide sequencing, we revealed that ILI and CTS mice, which are nondiabetic but are derived from the same Jcl-ICR mice as NOD mice, share the same class II MHC genes with NOD mice suggesting that both ILI and CTS mice also possess susceptible Idd-1 genotype. This was supported by a breeding study. To compare the usage of T cell receptor (TCR) V beta genes in NOD mice with that in ILI mice, we employed quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) which revealed that TCR V beta usages of these mice were indistinguishable. RT-PCR method also revealed that the V beta transcript of T cells infiltrating into pancreas of NOD mice was not restricted but was rather diverse. Since NOD and ILI mice share the same class I and II MHC antigens, we performed lymphocyte transfer experiments between these mice to examine the mechanism by which ILI mice do not develop insulitis. The results of reciprocal transfer of lymphocytes from NOD to ILI-nu/nu mice or from ILI to young NOD mice suggest that ILI mice exhibit autoantigens responsible for the development of insulitis but do not possess T cells reacting with islets. Of the diabetes-susceptibility genes, only in the case of Idd-1 is there any evidence for the identity of the gene products. ILI mice should provide more information on the products of the other diabetes-susceptibility genes of NOD mice.
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PMID:Molecular analysis of the pathogenesis of autoimmune insulitis in NOD mice. 780 6


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