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

The NOD mouse has been recently developed as a model for autoimmune insulin-dependent diabetes mellitus. The NOD mouse is further characterized by a genetic linkage with genes mapping within the major histocompatibility complex at the I-A locus. The present work demonstrates the presence in NOD mice of circulating autoantibodies specific for a 58 kDa antigen which is present in membrane extracts prepared from the murine insulin-secreting tumoral cell line Rin5F. This 58 kDa antigen shows a cross reactivity with NOD mouse class II antigens as indicated by its recognition by anti-I-A(NOD) monoclonal antibodies.
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PMID:[Cross-reactivity between major histocompatibility complex class II antigens in mice NOD and an islet antigen with 58 kDA molecular weight]. 250 91

This study provides a basis for understanding the wide variations reported in the literature in IFN-gamma inducibility of class II MHC antigens on murine beta cells. Inducibility is not an intrinsic property of all mouse beta cells, but instead depends upon strain- (and tissue-) specific response modifying factors. This was demonstrated by comparison of constitutive and IFN-gamma-induced class I and class II MHC gene products on cultured islet cell monolayers. Islet cultures were established from autoimmune diabetes-prone NOD/Lt mice, diabetes-resistant NON/Lt and CBA/J mice, as well as F1 hybrids between these latter two strains and NOD/Lt. Cultures of peritoneal macrophages (M phi) from each strain were established as controls. After 3 wk of culture (with incubation in the presence or absence of IFN-gamma during the last 6 d), constitutive expression as well as IFN-gamma induction of class I MHC antigen expression was demonstrated on NOD/Lt and NON/Lt islet cells by antibody plus complement-mediated cytotoxicity. Although CBA/J islets and M phi did not maintain constitutive class I or class II antigen expression in culture in the absence of IFN-gamma, class I H-2Kk antigen was IFN-gamma inducible. Whereas IFN-gamma-induced class II I-Ak antigen on CBA/J M phi, it failed to induce this antigen on CBA/J islets. In contrast, I-A antigens were IFN-gamma inducible on NOD/Lt and NON/Lt islets and M phi. In (CBA x NOD)F1 hybrids, loss of IFN-gamma inducibility of the I-ANOD product established that suppression was mediated by a trans-acting factor from the CBA/J genome. In the course of these studies, IFN-gamma inducibility of a crossreactive occult class I-like antigen on both NOD/Lt islet cell and M phi cultures was unexpectedly detected when mAb 28-13-3 (public specificity 39, reactive with H-2Kb,f) was used as a negative control. Although not detectable by cytofluorographic analysis of freshly isolated NOD/Lt splenic leukocytes, occult antigen could be induced on NOD/Lt peritoneal macrophages (M phi) cultured for 3 d in IFN-gamma. Time course of induction showed the occult antigen to be distinct from NOD/Lt class I and II gene products. In both islet cell and M phi cultures established from (CBA x NOD)F1 hybrids, trans-suppressive factor(s) from the CBA/J genome not only suppressed IFN-gamma-induced expression of I-ANOD, but additionally suppressed occult antigen induction. Backcross of F1 to both parental strains indicated that the occult locus was on Chr 17, tightly linked to MHC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:MHC antigen induction by interferon gamma on cultured mouse pancreatic beta cells and macrophages. Genetic analysis of strain differences and discovery of an "occult" class I-like antigen in NOD/Lt mice. 250 27

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

Diabetes in the NOD mouse strain is a genetically programmed T cell-mediated autoimmune process that is directed against an as yet unknown antigen target(s) on pancreatic beta cells. To investigate whether the course of the autoimmune disease could be altered by immune manipulations of the T cell repertoire, we have induced allogeneic tolerance by injecting F1 semiallogeneic spleen cells into NOD neonates. This procedure resulted in a significant protection against both insulitis and diabetes. However, although it requires the induction of tolerance, as shown by the failure of non-tolerizing irradiated cells to prevent autoimmunity, protection appeared to be independent of the major histocompatibility complex haplotypes of the F1 spleen cells injected at birth, e.g. (C57BL/6 x NOD)F1, (CBA/Ca x NOD)F1 or (BALB/c x NOD)F1 cells. In addition, a similar degree of protection was induced, whether the tolerant state, as assessed by mixed lymphocyte reaction studies in vitro, was of short duration, approximately 6 weeks, or lasted for more than 12 weeks. Putative veto or suppressor functions of chimeric T cells were ruled out, since mice tolerized with T cell-depleted F1 spleen cells were equally protected. We conclude that the expression of spontaneous T cell-mediated autoimmunity can be modulated by immune manipulations at birth. Whether the protection observed in the present experiments resulted from the production of one or several specific holes in the autoimmune T cell repertoire, i.e. cross-tolerance, or whether it resulted from nonspecific disturbances of the emerging T cell repertoire remains to be elucidated.
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PMID:Neonatal induction of allogeneic tolerance prevents T cell-mediated autoimmunity in NOD mice. 252 99

Genetic outcross and backcross analysis of nonobese diabetic (NOD/Lt) mice with a related but diabetes-resistant strain, nonobese normal (NON/Lt), has demonstrated that susceptibility to insulin-dependent diabetes mellitus is controlled in a recessive fashion by multiple genetic loci, including one (Idd-1s) associated with H-2 on chromosome 17 and another (Idd-2s) associated with Thy-1b/Apoa-1b (formerly Alp-1) on chromosome 9. To analyze the separate pathogenic contributions of Idd-1s and Idd-2s, two distinct congenic stocks of NOD/Lt mice homozygous on chromosomes 17 and 9 for NON/Lt linkage markers for the respective resistance alleles (Idd-1r and Idd-2r) were developed. The recessive nature of Idd-1s was confirmed at the fifth backcross generation in that 83% of females and 29% of males homozygous for NOD H-2 haplotype developed diabetes, whereas no diabetes occurred in any of the mice homozygous or heterozygous for the NON haplotype. However, codominant and recessive MHC-associated susceptibility genes in this congenic stock were indicated by the finding that at least one copy of the NOD/Lt MHC was required for insulitis development. Virtually no insulitis was detected in the pancreases of mice homozygous for NON haplotype at 42 wk of age, whereas heavy generalized insulitis was present in 3 of 19 H-2 heterozygotes and in 7 of 7 diabetic and 3 of 5 nondiabetic mice homozygous for NOD haplotype. Further indication of the presence of MHC-associated codominant and recessive MHC-associated susceptibility genes was the observation that the NOD MHC haplotype correlated in a codominant fashion with a relative increase in the percentage of splenic T-lymphocytes bearing the Ly-2 surface marker. Severe insulitis and concomitant high diabetes incidences occurred in all genotypic classes of congenic mice carrying Thy-1/Apoa-1 linkage markers for either NOD or NON alleles at Idd-2. Molecular analysis indicated that the NON-derived Idd-2r resistance allele had been replaced by recombination with Idd-2s from NOD. Restriction-fragment-length polymorphism analysis of two polymorphic markers proximal to Thy-1, low-density lipoprotein receptor Ldlr and Ets-1, a protooncogene, confirmed a recombinant chromosome 9, because homozygosity for NOD genomic fragments was found centromeric to an NON congenic segment of at least 20 centiMorgans spanning the Thy-1 and Mod-1 loci.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes 1989 Nov
PMID:Genetic control of diabetogenesis in NOD/Lt mice. Development and analysis of congenic stocks. 257 7

A large body of data generated during the past two decades has led to the ability to predict the development of Type I diabetes in the majority of relatives of diabetics. In particular we have recently proposed a dual parameter linear model to aid in predicting the onset of diabetes [years to diabetes = 1.5 + .03(IVGTT insulin secretion) - 0.008 (concn of insulin autoantibodies)]. The concentration of insulin autoantibodies in prediabetics appears to remarkably correlate with the age at which diabetes develops and the rate at which islet cell antibody-positive individuals progress to diabetes. Children developing diabetes before Age 5 often express more than 1000 nU/ml of such antibodies with the upper limit of normal of 39 nU/ml. Each prediabetic appears to be set at a characteristic level of insulin autoantibodies which does not consistently vary prior to the development of diabetes. During the prodromal phase preceding diabetes first phase insulin secretion is progressively lost, and the combination of insulin release which appears to reflect beta cell damage and the level of insulin antibodies accounts for more than 75% of the variation in time to diabetes over a 6-year interval. A subset of NOD mice also expresses insulin autoantibodies, and in addition essentially all NOD mice, but not F1 crosses of NOD by BALB/c, have antibodies to a target antigen of a RIN islet line protein (termed "polar antibodies"). In addition patients but not NOD mice have cytoplasmic islet cell antibodies which appear to react with a glycolipid islet target antigen. In the NOD mice the inheritance of disease is multigenic with a gene on chromosome 9, linked to the T cell marker theta, determining the bulk of islet cell destruction. In crosses of NOD mice with a series of normal strains, inheritance overt diabetes is correlated with inheritance of the NOD's unique I-A beta gene, though the bulk of islet destruction and insulitis can occur independent of MHC inheritance. Until the additional genes outside of the MHC, associated with the development of Type I diabetes, are identified for man, the NOD mouse, and the BB rat, one can only speculate concerning pathogenic mechanisms. To date islet cell destruction appears to be independent of polymorphic genes acting at the level of the islet target, and crucially dependent upon bone marrow precursor cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Type I diabetes mellitus: a predictable autoimmune disease with interindividual variation in the rate of beta cell destruction. 264 71

Anti-insulin autoantibodies were detected in NOD mice using ELISA. The antibodies were detected as early as at 5 weeks of age, long before onset of clinically overt diabetes, especially in diabetes-prone female mice. The anti-insulin specificity was verified by passage on affinity chromatography insulin columns and demonstration that the anti-insulin activity was located on the F(ab')2 region of the immunoglobulins. The presence of anti-insulin antibodies in prediabetic NOD mice provides a unique possibility for studying their significance and their eventual pathogenic role in the development of insulin-dependent diabetes.
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PMID:Insulin autoantibodies in non-obese diabetic (NOD) mice. 264 93

Antibodies to insulin appear prior to the development of Type I diabetes and their concentration may correlate with the rate of autoimmune beta cell destruction. In order to study potential mechanisms involved in the production of antibodies to insulin, we transplanted different strains of mice with histoincompatible non-islet cells (AtT20-Ins and NIH-3T3-Ins) synthesizing homologous insulin, in contrast to immunization with non-transfected cells and insulin in Freund's adjuvant. The pituitary cell line (AtT20) and the fibroblast cell line (NIH-3T3) were transfected with the rat insulin-II gene (which encodes an insulin molecule identical to that of mouse insulin-II). No antibodies to insulin were found after subcutaneous injection of AtT20-control cells (without the integrated rat insulin gene) or after injection of rat insulin complete Freund's adjuvant. After subcutaneous injections of living AtT20-Ins or NIH-3T3-Ins cells producing insulin (40 to 60 ng insulin/10(6) cells per injection) in two strains (BALB/cJ, C3H/HeJ) but not in a third (SJL/J), antibodies to insulin rapidly appeared. In addition, when AtT20-Ins cells were transplanted into Wistar-Furth rats, insulin antibodies appeared in three out of four animals. The level of antibodies induced was similar to the concentrations of insulin antibodies of prediabetic NOD mice. This finding suggests that during the immune destruction of a cell synthesizing insulin, humoral 'tolerance' to insulin can be rapidly abrogated. Genetic control of this response is suggested by the difference between response of BALB/cJ and C3H/He vs SJL/J.
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PMID:Production of insulin antibodies by mice rejecting insulin transfected cells. 266 99

Experimental results and therapeutic strategies. Insulin-dependent diabetes mellitus (IDDM) results from an autoimmune aggression toward beta cells in genetically predisposed individuals. Examination of the frequency of the different antigens coded by the major histocompatibility complex reveals an increased proportion of DR3-DQ2 and DR4-DQ8 haplotypes in IDDM subjects. Sequencing DQ-beta chains in such patients indicates the absence of aspartate in position 57 when compared to control individuals. Islet cell cytoplasmic autoantibodies are early markers of ongoing autoimmunity in addition to insulin autoantibodies before administration of exogenous insulin. Experimental models of autoimmune diabetes like the NOD (NonObese Diabetes) mouse underline the predominant role of T lymphocytes in the constitution of both insulitis and beta cell destruction. In humans, an increased proportion of activated T lymphocytes can be observed but is not specific of the disease. This underlines the need for new cellular markers of the autoimmune process. Transgenic mice allow studies on the consequences of abnormal expression of new molecules on beta cell surface like cytokines or MHC class II molecules which represent a new field of investigation on the pathogenesis of IDDM. Prospective studies in first degree relatives of type I diabetic patients indicate the existence of an asymptomatic phase of beta cell destruction where specific autoimmune markers can be individualized. In some individuals abnormal insulin response to glucose--loss of first phase insulin release during intravenous glucose tolerance test--precedes insulin deficiency. The identification of an autoimmune process leading to beta cell destruction allows new therapeutic approaches with immunointervention at early stages of the disease.
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PMID:[Autoimmunity and insulin-dependent diabetes mellitus. Experimental data and therapeutic prospects]. 267 68

Walter & Eliza Hall Institute nonobese diabetic (NOD/Wehi) mice exhibit a low incidence of spontaneous diabetes mellitus, but one large dose of cyclophosphamide (CY) can lead to a rapid progression to overt diabetes. Macrophages and Lyt-2+ and L3T4+ cells have been demonstrated to be involved in beta-cell destruction in this model. The role of a specific subset of T-lymphocytes expressing a particular T-lymphocyte-receptor segment was examined in CY-induced diabetic NOD mice with a mouse anti-V beta 8 T-lymphocyte-receptor monoclonal antibody (F23.1). After administration of CY, only 4 of 51 treated mice became hyperglycemic compared to 23 of 47 untreated mice, 13 of 26 mice treated with an isotype-matched control ascites, and 4 of 6 mice given antibody-negative ascites. Insulitis was significantly reduced in the F23.1-treated group, and immunocytochemistry revealed the absence of V beta 8 expression on cells in the lymphoid organs and insulitis of these mice. This investigation revealed that V beta 8+ cells were implicated in CY-induced diabetes in NOD/Wehi mice.
Diabetes 1989 Nov
PMID:Prevention of cyclophosphamide-induced diabetes by anti-V beta 8 T-lymphocyte-receptor monoclonal antibody therapy in NOD/Wehi mice. 269 77


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