Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4+ lymphocytes are the most important effector cells in autoimmune diabetes of NOD mice, although some role of CD8+ T cells has been demonstrated. However, it is unknown how CD4+ lymphocytes are able to destroy pancreatic beta-cells that do not express MHC (major histocompatibility complex) class II molecules. Apoptotic cell death mediated by an interaction of Fas with Fas ligand (FasL) could be a mechanism by which MHC class II-negative pancreatic beta-cells are destroyed by CD4+ T lymphocytes. We have examined the expression of Fas molecules in pancreatic islet cells, as well as in a NOD-derived mouse insulinoma cell line (MIN6N8). In addition, the role of Fas-mediated apoptosis in pancreatic islet cell death was explored in vitro. Although Fas expression was not detected by flow cytometric analysis, Fas transcripts were demonstrated in MIN6N8 cells and pancreatic islet cells by the sequencing analysis of the cloned reverse transcription polymerase chain reaction products using Fas-specific primers. IFN (interferon)-gamma, tumor necrosis factor-alpha, interleukin-1 and their combinations failed to enhance Fas expression. Unsorted activated splenocytes from diabetic NOD mice had cytotoxic T lymphocyte activity of a small degree against IFN-gamma-treated MIN6N8 cells with FasL upregulation. However, agonistic anti-Fas antibody with or without cycloheximide did not exert cytotoxicity against MIN6N8 cells or pancreatic islets. FasL transfectant cells also did not kill MIN6N8 cells. Our data indicate that pancreatic beta-islet cells express a small amount of Fas molecules but Fas molecules do not mediate apoptosis of islet cells at least in vitro.
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PMID:Fas is expressed in murine pancreatic islet cells and an insulinoma cell line but does not mediate their apoptosis in vitro. 1043 99

We evaluated two bone marrow-derived dendritic cell (DC) populations from NOD mice, the murine model for type 1 human diabetes. DCs derived from GM-CSF [granulocyte/macrophage colony-stimulating factor] + interleukin (IL)-4 cultures expressed high levels of major histocompatibility complex (MHC) class II, CD40, CD80, and CD86 molecules and were efficient stimulators of naive allogeneic T-cells. In contrast, DCs derived from GM-CSF cultures had low levels of MHC class II costimulation/activation molecules, were able to take up mannosylated bovine serum albumin more efficiently than GM + IL-4 DCs, and were poor T-cell stimulators. The two DC populations migrated to the spleen and pancreas after intravenous injection. To determine the ability of the two DC populations to modulate diabetes development, DCs were pulsed with a mixture of three islet antigen-derived peptides or with medium before injection into prediabetic NOD mice. Despite phenotypic and functional differences in vitro, both populations prevented in vivo diabetes development. Pulsing of the DCs with peptide in vitro did not significantly improve the ability of DCs to prevent disease, which suggests that DCs may process and present antigen to T-cells in vivo. In addition, we detected GAD65 peptide-specific IgG1 antibody responses in DC-treated mice. Overall, these results suggest that a Th2 response was generated in DC-treated mice. This response was optimal when using GM + IL-4 DCs, which suggests that the balance between regulatory Th2 and effector Th1 cells may have been altered in these mice.
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PMID:Immunotherapy of NOD mice with bone marrow-derived dendritic cells. 1058 Apr 17

The common Kd and/or Db alleles of NOD mice contribute to the development of autoimmune diabetes, but their respective contributions are unresolved. The major histocompatibility complex (MHC) of the CTS/Shi mouse, originally designated as H2ct, shares MHC class II region identity with the H2g7 haplotype of NOD mice. However, CTS mice were reported to express distinct but undefined MHC class I gene products. Because diabetes frequency was reduced 56% in females of a NOD stock congenic for H2ct, this partial resistance may have derived from the MHC class I allelic differences. In the present report, we use a combination of serologic analysis and sequencing of MHC class I cDNAs to establish that NOD/Lt and CTS/Shi share a common H2-Kd allele but differ at the H2-D end of the MHC complex. The H2-D allele of CTS/Shi was identified as the rare H2-Ddx recently described in ALR/Lt, another NOD-related strain. These results in mouse model systems show that multiple MHC genes confer diabetes resistance and suggest that at least one of the protective MHC or MHC-linked genes in CTS mice may be at the H2-D end of the complex.
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PMID:Reevaluation of the major histocompatibility complex genes of the NOD-progenitor CTS/Shi strain. 1061 61

Transgenic techniques in inbred mouse strains are powerful tools to investigate the specific roles of genes in biological pathways and disease models. However, there is increasing concern over the influence of a variable genetic background in such experiments. To date there have been few investigations of the immunological differences between inbred mouse strains used in models of autoimmune diseases. Here we phenotyped lymph node cells and T-cell cytokine production in B10.Q (H2q), B10.RIII (H2r), C3H.Q (H2q), C3H. NB (H2p), NOD (H2g7), RIII/SJ (H2r) and DBA/1J (H2q) mice. We found several significant differences. The C3H strains and RIII/SJ lymph node cells had a high ratio of T cells/B cells (> 2 : 1) and a high ratio of CD4/CD8 positive cells (> 3 : 1), these strains are therefore denoted high T cell ratio (HiTR) strains. B10 strains and DBA/1, however, displayed an expansion of gammadeltaT cells after mitogen activation. T cells derived from C3H and DBA/1J strains produced more interleukin (IL)-4 than did T cells from B10 and NOD strains. DBA/1J and B10.Q showed a 10-fold increase in interferon (IFN)-gamma producing cells in the CD4+ T-cell population. Variation in the number of IL-2 and IFN-gamma producing T cells between the B10 major histocompatibility complex (MHC) congenic strains was the only difference possibly controlled by the MHC region. We conclude that non-MHC genes influence the numbers of T cells and B cells in lymph nodes, as well as IFN-gamma, IL-4 and IL-10 production by T cells.
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PMID:Non-major histocompatibility complex dependent variations in lymphocyte activity between inbred mouse strains susceptible to various autoimmune diseases. 1088 80

The major histocompatibility complex (MHC) is the most important susceptibility locus for type I diabetes in humans and NOD mice. NOD mice express a single MHC class II molecule (I-Ag7) which carries a unique beta chain sequence. In humans, DQ alleles that encode DQ8 and DQ2 confer the highest risk for the disease. Soluble DQ8 and I-Ag7 were used to directly compare the binding specificity of these MHC molecules. Peptides from three islet antigens--insulin, GAD 65 and HSP 60--bound to both CQ8 and I-Ag7. These peptides included epitopes that are immunodominant in NOD mice, namely insulin (9-23), GAD (206-220) and HSP 60 (441-460). All of these peptide sequences are highly conserved between the human and murine antigens. The binding specificity of DQ8 and I-Ag7 was similar, but not identical, since two peptides eluted from splenocytes of NOD mice did not bind to DQ8. DQ8 formed long-lived complexes with the majority of these peptides, indicating that DQ8 is not a poor peptide binder. These results demonstrate functional similarities between human and murine MHC class II molecules that confer susceptibility to type I diabetes.
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PMID:Binding of conserved islet peptides by human and murine MHC class II molecules associated with susceptibility to type I diabetes. 1100 82

NOD mice spontaneously develop anti-insulin autoantibodies and diabetes. A dominant peptide recognized by T-cell clones from NOD mice is insulin B-chain peptide B9-23. When administered subcutaneously to NOD mice, this peptide decreases the development of diabetes. In this study, we evaluated the autoantibody response to native insulin after administration of the B9-23 peptide. In NOD mice, administration of the B9-23 peptide in incomplete Freund's adjuvant enhanced their insulin autoantibody response with a higher level and longer persistence. Induction of insulin autoantibodies with the B9-23 peptide was observed in non-diabetes-prone BALB/c mice and NOR mice within 2 weeks of administration, but this was not observed in C57BL/6 mice. A series of A-chain, other B-chain, and proinsulin peptides did not induce insulin autoantibodies. Induced anti-insulin autoantibodies could not be absorbed with the peptide alone but could be absorbed with native insulin. The B13-23 peptide (one of two identified epitopes within B9-23) when administered to BALB/c mice, induced autoantibodies, whereas peptide B9-16 did not. Induction of autoantibodies mapped to the major histocompatibility complex (MHC) rather than to the background genes. Both splenocytes with I-A(d)/I-E(d) or I-A(g7)/I-E(null) presented the B9-23 peptide to NOD islet-derived T-cell clones. Finally, administration of the B9-23 peptide to BALB/c mice, even without adjuvant, could induce insulin autoantibodies. Our results indicate that B-cell tolerance to intact insulin is readily broken with the presentation of the B9-23 insulin peptide, depending on the host's specific MHC.
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PMID:Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice. 1137 27

For poorly understood reasons, the development of autoimmune diabetes in humans and mice is dominantly inhibited by major histocompatibility complex (MHC) class II molecules with diverse antigen-binding sites. We have previously shown that thymocytes expressing a highly diabetogenic I-A(g7)-restricted T-cell receptor (TCR) (4.1-TCR) undergo negative selection in mice carrying one copy of the antidiabetogenic H-2(b) haplotype in an I-A(b)-dependent but superantigen-independent manner. Here, we show that 4.1-TCR-transgenic thymocytes undergo different forms of tolerance in NOD mice expressing antidiabetogenic I-A(d), I-A(g7PD), or I-Ealpha(k) transgenes. The ability of protective MHC class II molecules to induce thymocyte tolerance in 4.1-TCR-transgenic NOD mice correlates with their ability to prevent diabetes in non-TCR-transgenic mice and is associated with polymorphisms within positions 56-67 of their beta1 domains. The 4.1-thymocyte tolerogenic activity of these MHC class II molecules is mediated by dendritic cells and macrophages but not by B-cells or thymic epithelial cells and is a peptide-dependent process. Antidiabetogenic MHC class II molecules may thus afford diabetes resistance by presenting, on dendritic cells and macrophages, tolerogenic peptides to a subset of highly diabetogenic and MHC-promiscuous CD4(+) T-cells that play a critical role in the initiation of diabetes.
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PMID:T-cell tolerance by dendritic cells and macrophages as a mechanism for the major histocompatibility complex-linked resistance to autoimmune diabetes. 1181 39

Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent autoimmunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac transplants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)-matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recipients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with better MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allografts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation.
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PMID:The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade. 1240 11

Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet beta cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.
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PMID:Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes. 1241 28

Vaccinating mice with DNA encoding the thyrotropin receptor (TSHR), the major autoantigen in Graves' disease, induces memory T cells that secrete interferon-gamma (IFN-gamma) in response to TSHR antigen. We used a panel of 29 synthetic TSHR peptides encompassing the ectodomain and three extracellular loops to identify T-cell epitopes after TSHR-DNA vaccination of BALB/c, NOD.H-2h4, and AKR/N mice. These strains were chosen because of their previous use in animal models of thyroid autoimmunity. In initial studies, challenge of splenocytes with TSHR protein induced IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) production in all three strains of mice. BALB/c mice recognized three peptides, all in the TSHR A subunit. These peptides differed from the four peptides recognized by nonobese diabetic (NOD mice NOD H-2h4). Three of the latter were also in the A subunit. The fourth was within the intervening C peptide region excised on TSHR cleavage into A and B subunits. Because of high and erratic responses in AKR/N mice, their TSHR T-cell epitopes could not be determined. In summary, we report that TSHR DNA vaccination of BALB/c and NOD.H-2h4 mice, with different major histocompatibility complex (MHC) class II genes (I-Ad and I-Ak, respectively), recognize restricted, nonoverlapping TSHR T-cell epitopes, nearly all in the TSHR A subunit.
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PMID:Peptide scanning for thyrotropin receptor T-cell epitopes in mice vaccinated with naked DNA. 1248 40


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