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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Until recently, localization of genes involved in multifactorial diseases, such as diabetes, was thought to be impracticable. The recent development of microsatellite genetic markers detected by PCR has facilitated detailed genetic analysis of complex traits. Microsatellite markers have been utilized for genetic analysis of NOD mice which spontaneously develop autoimmune IDDM similar to the human disease. There is evidence for ten distinct loci that affect the development of insulitis and diabetes in NOD mice. One of these loci, designated Idd-1, has been linked to the MHC on chromosome 17. Transgenic mouse experiments have shown that Idd-1 is composed of MHC class II genes I-A beta and I-E alpha.
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PMID:[Current studies on the identification of susceptibility genes for IDDM in NOD mice]. 798 13

IDDM is unquestionably an autoimmune disease, as reflected by the presence of beta-cell-reactive autoantibodies and T cells, T cell-mediated transfer of the disease in nondiabetic mice, rats, and humans, and disease sensitivity to immunosuppressive therapy. T cells are predominantly, if not exclusively, involved in creating the islet lesions that lead to beta-cell atrophy after a stage of reversible inflammation. A full understanding of the disease pathogenesis will require a better definition of the nature of the triggering and target autoantigen(s) and of the effector mechanisms (cytokines, cytotoxic cells?). Much less information is available on the etiology than on the pathogenesis. Genetic factors are mandatory and the involvement of predisposition genes (HLA and non-HLA) is now being unravelled. The modulatory role of environmental factors is demonstrated by the high disease discordance rate in identical twins and by experimental data showing positive and negative modulation of the disease by a number of agents, notably infectious agents and food constituents. It is not clear, however, whether a given environmental factor, e.g. a precise virus or a cow's milk component, plays a real etiological role in a selected genetic background. IDDM thus appears as a multifactorial disease. It is not known, however, whether all factors intervene concomitantly in a given individual or separately in subsets of patients, explaining the clinical heterogeneity of the disease. The mechanisms underlying the loss of tolerance to self beta-cell autoantigen(s) are still unknown. Defective intrathymic negative selection of autoantigen-specific autoreactive T cell clones is unlikely. Breakdown of T cell anergy could occur according to various mechanisms, including aberrant expression of MHC molecules and molecular mimicry. Defective suppressor T cell function, perhaps related to TH1/TH2 imbalance, probably intervenes by amplifying the anti-beta-cell autoimmune response whatever its triggering mechanism. Before putative etiological agents are identified, one must base immunotherapy on nonantigen-specific agents. Results recently obtained in NOD mice indicate that the goal of nontoxic long-lasting immune protection from the disease is feasible if treatment is started early enough. In some cases (anti-T cell monoclonal antibodies), it appears that specific unresponsiveness can be induced. This double strategy (early intervention, tolerance induction) is the main challenge for immunodiabetologists.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin-dependent diabetes mellitus as an autoimmune disease. 798 84

The NOD mouse strain has become one of the most popular animal models for exploring insulin dependent type 1 diabetes. Genetic studies have underlined the polygenic nature of the murine disease. Two such genes were mapped on chromosome 1. One, associated with diabetes onset, is strongly linked with the Lsh, Ity, bcg genes encoding for resistance against L. donovani, S. typhimurium and Mycobacterium. We have undertaken to phenotype NOD mice with regard to one of these resistance genes. After infection with Salmonella abortusovis, we found that NOD mice bore the resistant phenotype/Ityr, which is responsible for early resistance against Salmonella infection.
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PMID:Resistance of NOD mice to salmonellosis. 804 1

Early therapy made possible by the predictive tests discussed above, using selective or even antigen-specific therapy, opens the way to more radical and much more innocuous therapeutic approaches of major AIDs. It should be realized, however, that before the putative autoantigens have been identified, immunotherapy must be based on nonantigen-specific agents. The results recently obtained in NOD mice indicate that the goal of nontoxic, long-lasting immune protection from the disease is feasible if treatment is started early enough. In some cases (anti-T cell monoclonal antibodies), it appears that specific unresponsiveness can be induced even in the absence of a concomitant administration of the autoantigen. In the case of IDDM, one must convince clinical diabetologists, patients, and their families that immunoprevention of the disease will only be achieved if research on both prediction and immunotherapy proceeds hand in hand: prediction programs are difficult to run without proposing access to preventive therapy, and the search for therapy cannot be successful without access to prediabetics or patients with preclinical diabetes and they can only be identified in prediction clinics. In brief, the two research approaches, prediction and specific therapy, have to be carried out in parallel until their convergence allows the final immunoprevention of the disease.
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PMID:Predictive medicine in autoimmune diseases: from the identification of genetic predisposition and environmental influence to precocious immunotherapy. 805 Jan 86

To localize and characterize the MHC-linked diabetogenic gene of the NOD mouse, we studied the class III region of the MHC in the NOD mouse and related strains. Hsp70, Bat5, Tnfa and Tnfb loci were studied by microsatellite polymorphism analysis and/or restriction mapping. The CTS mouse had the same allele as the NOD mouse at the Hsp70 locus, but different alleles at the Bat5, Tnfa and Tnfb loci from those of the NOD mouse. Our previous studies indicated that in the CTS mouse, class II MHC was the same as that of the NOD mouse, but that class I MHC was different at both K and D loci, and that CTS MHC was diabetogenic in the presence of NOD background genes. These data map major genetic susceptibility to type 1 diabetes to the segment flanked by class I K and class III Bat5 loci. Moreover, since the diabetogenic effect of the CTS MHC is weaker than that of the NOD MHC, these data suggest the presence of a second MHC-linked gene or gene complexes that modulate susceptibility to type 1 diabetes outside this segment.
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PMID:MHC-linked diabetogenic gene of the NOD mouse: molecular mapping of the 3' boundary of the diabetogenic region. 809 12

The NOD mouse, which spontaneously develops insulitis and overt diabetes, is a model of autoimmune type I diabetes mellitus. To analyze of the roles of CD4+ and CD8+ T cells in the pathogenesis of this mouse, we have been doing a series of studies on the induction of insulitis and diabetes in NOD athymic nude mice by means of T cell transfer. To complement our previous study dealing with the induction of insulitis and cyclophosphamide-induced diabetes in recipients that had been reconstituted with each T cell subset derived from the nondiabetic mice, the present study was conducted to observe the transfer of spontaneous diabetes by injecting T cells harvested from diabetic mice. Any possible in vivo increase in the contaminating T cell subset was prevented by injecting the antibody homologous to it. Transfer of untreated or complement-treated splenic lymphocytes of diabetic mice containing both T cell subsets induced spontaneous diabetes 30 to 58 days after the cell transfer as well as insulitis, while spleen cells from nondiabetic mice rarely produced diabetes. On the other hand, transfer of either CD4+ cell-depleted or CD8+ cell-depleted splenic lymphocytes of diabetic mice did not cause diabetes at least up to 60 days after the cell transfer. Also, transfer of only the CD4+ T cell-depleted fraction did not cause insulitis. In contrast, transfer of only the CD8+ T cell-depleted fraction induced insulitis in all the recipients. However, insulitis was less potent in this group of mice than in the diabetic recipients given both subsets: only a low insulitis score was obtained and a number of beta-cells remained alive despite the insulitis in mice given the CD8+ T cell-depleted fraction, whereas islet damage was very severe and insulin-secreting beta-cells were no longer detected in the diabetic mice. Thus, the present results agree with the previous ones concerning transfer of diabetes, with the aid of cyclophosphamide treatment, by T cells of nondiabetic mouse origin. Consideration of our results together with earlier findings led to the conclusion that CD4+ T cells are primarily responsible for insulitis and that CD8+ T cells migrate into islets and are differentiated into mature killer cells against beta-cells with the aid of CD4+ T cells in both spontaneous and cyclophosphamide-induced diabetes.
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PMID:Transfer of autoimmune diabetes from diabetic NOD mice to NOD athymic nude mice: the roles of T cell subsets in the pathogenesis. 809 66

The 12th International Immunology of Diabetes Workshop was held during April 1993 in Orlando, Florida, to review research progress since the 11th Immunology of Diabetes Workshop meeting in Nagasaki, Japan, one and a half years before. The NOD mouse may have as many as 10 susceptibility genes, including its novel IA major histocompatibility complex antigen and a defective interferon-gamma receptor, whereas human IDDM is so far known to be encoded by cis and trans complementation products of certain DQ genes on chromosome 6q, and a gene in the insulin-like growth factor II region on chromosome 11p. A unique protein regulator of the X box promotor of the highly susceptible DQB1*0302 allele has also been found. Islet cell antibody negative siblings of IDDM patients appear to have lower than expected abilities to secrete insulin in response to intravenous glucose. Sera from patients before and/or after developing IDDM immunoprecipitate two native proteins of 64,000- and 38,000-M(r) glutamic acid decarboxylase (GAD65) reacting to conformational epitopes. However, a multitude of other autoantibodies often reacting to denatured proteins through linear epitopes have also been identified. The first workshop for GAD antibody assays was successfully completed; however, the 38,000-M(r) antigen has not yet been identified. Other autoantibodies reactive to gangliosides and to sulfatides continue to be reported. Insulitis has come to be recognized as a sometimes protective event. Protective insulitis predominates in older lesions. It can be induced by as disparate means as tuberculin antigen administration, by interleukin-4 treatments, by transfer of T-cell lines generated in autologous mixed lymphocyte responses, and by immunization to insulin B-chain, whereas oral islet cell antigens, such as insulin, can delay diabetes onset in the NOD mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The 12th International Immunology and Diabetes Workshop. Orlando, Florida. 810 Jul 86

Our experiments imply that it is possible to use monoclonal antibody therapy to reestablish self tolerance to self antigens. This can be achieved by using a short course of an nd anti-CD4 antibody thus avoiding the problem of long term immunosuppression. The mechanism by which such a state of self tolerance is achieved remains to be clarified but possible mechanisms include deletion or anergy of autoreactive T cells or some form of suppression mediated through local cytokine production. As this antibody induced state of tolerance can be reversed in the NOD mouse by cyclophospamide deletion cannot be the method by which autoreactivity is prevented. The mixing experiments which have been described in the thyroiditis experiments strongly suggest that anery is not the mechanism. It therefore remains most likely that tolerance induced following administration of nd anti-CD4 is an active process maintained through the production of an inhibitory cytokine. This ability to reprogram the immune system using monoclonal antibodies makes it not beyond the realms of possibility that individuals suffering from IDDM may become tolerant of their beta cell antigens and thus be able to regenerate their own beta cell mass. If this could indeed occur it might mean that a lifetime of insulin injections and the development of the life threatening complications that may accompany a disease like IDDM may be avoided.
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PMID:The regulation of autoimmunity through CD4+ T cells. 810 91

We have studied the effects of long-term treatment with azathioprine (AZA) vs cyclosporin A (CSA) vs placebo (PL), in three groups of 10 week old, prediabetic NOD mice. One of 8 AZA, none of 8 CSA and 7 of 11 PL treated mice developed overt diabetes (IDDM). Quantitative morphometric analysis conducted on mouse pancreatic histologic sections documented that extent and degree of islet beta-cell damage were incomparably less severe in the mice that received AZA or CSA compared to those treated with PL. Since early and prolonged treatment with AZA seems to prevent the onset of DM in NOD mice as nearly effectively as CSA, AZA, which is significantly safer than CSA, could replace the latter as a potential approach for the immunotherapy of IDDM.
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PMID:Preventive effects of azathioprine (AZA) on the onset of diabetes mellitus in NOD mice. 814 63

GAD is a major islet cell autoantigen in human type 1 diabetes mellitus. Autoantibodies are preferentially directed against the 65-kD isoform of the enzyme which is the only form expressed in human islets of Langerhans. The NOD mouse is a spontaneous model of type 1 diabetes, frequently employed in studies dealing with the immunopathogenesis of the disease. In the present study the reactivity of sera from 34 prediabetic and 15 diabetic NOD mice was tested against GAD protein present in islets of Langerhans and cerebellum, and against recombinant, semi-purified GAD-65 and GAD-67. A rabbit antiserum (K2) raised against GAD-67 could readily recognize the recombinant GAD-67 and the isoform present in rat and mouse islets and mouse brain. A MoAb (GAD-6) specific for the GAD-65 isoform reacted against the recombinant GAD-65 and the isoform present in rat islets and mouse brain, whereas no reactivity was observed when using mouse islets. However, when testing the NOD mice sera by immunohistochemistry, immunoprecipitation and Western blot, no reactivity against any of the isoforms of GAD could be detected. Using reverse transcription polymerase chain reaction (PCR), GAD-67 mRNA could be detected in mouse and rat islets and in mouse brain. GAD-65 mRNA could also be detected in rat islets and mouse brain, but apparently a much lower copy number is present in mouse islets. These findings stress important differences in the immune response occurring in the animal model NOD mouse compared with human type 1 diabetes, and emphasize that human and animal type 1 diabetes possibly represent the final outcome of several different etiological factors.
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PMID:Absence of autoantibodies against glutamate decarboxylase (GAD) in the non-obese diabetic (NOD) mouse and low expression of the enzyme in mouse islets. 814 57


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