Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NOD mice were treated with silica (which is selectively toxic to macrophages) from 4 or 20.5 wk of age. Syngeneic neonatal pancreases were transplanted into the renal subcapsular space of the NOD mice at 21 wk of age. Silica treatment was continued until 24 wk of age, and then the mice were killed for examination of islet morphology. Neither the islets in transplanted pancreases nor the host pancreatic islets from the early long-term silica-treated animals revealed insulitis. In contrast, most of the islets in transplanted pancreases from the late short-term silica-treated animals showed severe insulitis and beta-cell necrosis, as did the host islets. A further experiment was performed to compare the effect of late short-term silica treatment with that of anti-L3T4-antibody treatment of the same time and duration. In contrast to the late short-term silica-treated animals, the transplanted pancreases in the anti-L3T4-antibody-treated animals revealed intact islets, although most of the host islets showed insulitis. The control group, which received no treatment but did receive neonatal pancreases, revealed severe insulitis and beta-cell necrosis of both transplanted and host islets. These results suggest that early macrophage depletion can abolish the development of beta-cell-specific immunologic effectors but that late macrophage depletion, after the development of insulitis, does not affect the destruction of beta-cells by preexisting effectors other than macrophages. We conclude that macrophages are essential for the development of beta-cell-specific cytotoxic effectors in the initial phase of insulitis in NOD mice.
Diabetes 1990 Oct
PMID:Studies on autoimmunity for initiation of beta-cell destruction. VI. Macrophages essential for development of beta-cell-specific cytotoxic effectors and insulitis in NOD mice. 217 Feb 17

The morphological basis of type-I diabetes is the destruction of the islets of Langerhans by an inflammatory process. Immunosuppressive and immunomodulatory mechanisms can prevent diabetes in NOD-mice and BB-rats when given before onset of the disease. In man at the time of diagnosis of diabetes insulitis has progressed already to a loss of more than 80% of the Beta-cells. Several immunosuppressive drugs and immunobiological regimen may influence the course of the disease only in the sense of a temporary remission. Cyclosporine-A was the most effective drug, but can not be recommended for general use at present time because of side effects on the kidney at least when given in higher doses. Whether minimizing the effective dose will be equally effective remains open. Other drugs as ciamexone which seems to be safer have to be taken into account for further studies. Suppression of insulitis most probably will be more successful when the treatment starts at an earlier phase i.e. before onset of the disease. The criteria at what time this may be justified have to be elaborated.
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PMID:Specific therapeutic attempts in experimental and clinical type-I diabetes. 219 89

Very little is known about the genes involved in the pathogenesis of IDDM. One component is known to be linked to the major histocompatibility complex, but the other components are unknown. We know from the major animals models of IDDM, both the NOD mouse and the BB rat, that the disease is under multigenic control. However, due to the size and complexity of the mammalian genome as well as to the lack of useful clues, the location and identity of the other genes remains a mystery. This is compounded by the fact that well-characterized genetic markers are not available for all regions of the mammalian genome, and it is likely that at least some of the genes of interest are located in these regions. The testing of pedigrees for the linkage of RFLP with the genetic factors involved in IDDM promises to be the most effective means of mapping, and ultimately identifying, these genes. However, the number of genes which are theoretically necessary to test for linkage makes even this approach impractical. Here, we have described here how the amount of work and time can be significantly reduced by utilizing repetitive DNA sequences as probes for the linkage of random RFLPs to diabetes. With each screening, one can simultaneously test multiple unlinked loci in the genome. Preliminary results which show promising linkage to two of the genetic components have been presented, thereby supporting the usefulness of this approach.
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PMID:The genetics of insulin-dependent diabetes in the BB rat. 219 68

We have previously shown the presence of circulating islet cell cytoplasmic antibodies (ICA) and insulin autoantibodies (IAA) in the NOD mouse before onset of insulin-dependent diabetes mellitus (IDDM). Here we have determined the levels of the two autoantibodies in 28 female NOD mice longitudinally from approximately day 40 to day 250, to examine their ontogeny, association and predictive value for diabetes. All animals (11 diabetic, 17 non-diabetic) showed varying levels of ICA at some stage, while IAA activity was found in 21 out of 28 mice. Expression of both the markers was seen in more than half of the animals by day 60, with higher levels and rates occurring subsequently in both diabetic and non-diabetic groups. The expression of ICA did not always correlate with that of IAA. There was no apparent difference in the ontogeny of ICA and IAA between the two groups. During the study period the number of animals with ICA was similar in the two groups, while the number of those with IAA was higher in the diabetic animals. In this group declining and rising levels of ICA were seen just before clinical diabetes with frequent peaks of IAA. In the same animals, eight out of 11 mice showed co-expression of high levels of both markers either intermittently or persistently prior to onset, whereas only one non-diabetic animal showed this. We conclude that the ontogeny and serum level of ICA or IAA alone could not be used to predict the clinical onset of diabetes in these animals. However, co-expression of high levels of both markers prior to onset may suggest a strong predisposition to clinical diabetes. This may have relevance to attempts to predict the onset of IDDM in humans who have one or both of these immunological markers.
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PMID:Longitudinal study of islet cell antibodies and insulin autoantibodies and development of diabetes in non-obese diabetic (NOD) mice. 220 3

Insulin-dependent diabetes is the direct consequence of an autoimmune reaction causing the destruction of the beta cells of the islets of Langerhans in the pancreas. The frequent association of diabetes with other diseases involving the immune system, the detection of circulating antibodies aimed at the islet cells, the occurrence of the disease in subjects with peculiar HLA antigens are as many arguments supporting the immunological hypothesis. The study of animal models of insulin-dependent diabetes (BB rats, NOD mice) now allows demonstrating the autoimmune process. The transient effectiveness of cyclosporin demonstrated in the human disease confirms these data. The prospects of transplantation of the pancreas, of islets or of islet cells in diabetic subjects to compensate for the insulin deficiency therefore raises the double immunological problem of allogenic rejection and of the risk of recurrence of the anti-islet autoimmune disease.
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PMID:[Diabetes mellitus and autoimmunity]. 229 24

Cyclosporine prevents the development of diabetes in spontaneously diabetic BB rats and NOD mice. However, islet transplants have been shown to be subject to immunologic destruction in hosts treated with CsA and anti-CD4 antibody or those rendered tolerant to donor antigens. This study determines whether the minimum dose of CsA necessary to prevent rejection of pancreatic transplants will also prevent recurrent diabetes in pancreas transplants in BB rats. Lewis recipients promptly reject BN (n = 13, MST 9.2 +/- 0.7 days) and Fisher (n = 6, MST = 11.3 +/- 0.8 days) pancreatic transplants. Treatment with CsA 5 mg/kg/day 0-50 days posttransplant and 2 mg/kg/day 51-100 days (low-dose CsA) produced indefinite survival of BN (n = 5) but not Fisher (n = 4) allografts. Fisher allografts were uniformly successful if maintained on 5 mg/kg/day (n = 4). Treatment with CsA 5 mg/kg/day for 14 days had no deleterious effect on glucose tolerance in Lewis isografts (control [K = 1.81 +/- 0.24, n = 8] vs. CsA treated [K = 1.76 +/- 0.20, n = 8, P = NS]). Low-dose CsA ensured permanent survival of MHC-compatible WF (n = 7, MST greater than 115 days) and MHC-incompatible BN (n = 9, MST greater than 117 days, P = NS) pancreatic transplants in spontaneously diabetic BB/Wor hosts. Three of 11 recipients surviving greater than 100 days enjoyed seemingly permanent acceptance of their allografts after discontinuation of CsA. Immunocompetence was demonstrated by rejection of their pancreas transplants when challenged with donor skin. Vascularized pancreatic allografts treated with CsA appear to be less vulnerable to recurrent diabetes than are islet transplants. Low-dose CsA protects vascularized pancreatic allografts in BB rats from both rejection and recurrent diabetes.
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PMID:Evidence that cyclosporine prevents rejection and recurrent diabetes in pancreatic transplants in the BB rat. 233

The immune abnormalities of NOD mice, a model of human type I (insulin-dependent) diabetes, have been postulated to be T-lymphocyte dependent. We measured responsiveness to exogenous interleukin 2 (IL-2) and IL-2 production in spleen mononuclear cells from female NOD/Shi/Kbe mice after stimulating the cells with concanavalin A (ConA blasts) or phytohemagglutinin (PHA blasts). Exogenous IL-2 produced significantly lower proliferative responses in each blast from 3- and 10-wk-old NOD/Shi/Kbe mice than from control strains. IL-2 production in NOD/Shi/Kbe mice was inclined to decrease but not significantly compared with controls. Even sufficient amounts of recombinant IL-2 (rIL-2) or IL-1 (rIL-1), added with mitogens to the preculture medium, failed to provoke normal proliferative responses from NOD/Shi/Kbe mouse cells. To clarify the reason for this defect, we investigated the expression of IL-2 receptors (IL-2Rs) on mitogen-activated cells with anti-IL-2R monoclonal antibody (PC61) and radiolabeled IL-2. Cytofluorometry showed no significant difference between strains in the number of PC61+ ConA and PHA blasts. However, Scatchard analysis with 125I-labeled IL-2 showed that the number of high-affinity IL-2Rs (H-IL-2Rs), the mediators of the biological activity of IL-2, was decreased in NOD/Shi/Kbe mice compared with controls, whereas the number of low-affinity IL-2Rs (L-IL-2Rs) was not different. Separating the L3T4+ and Lyt-2+ populations of T lymphocytes by cell sorting showed both to be deficient in H-IL-2Rs.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 Sep
PMID:Impaired mitogen-induced expression of high-affinity interleukin 2 receptors on spleen cells from NOD/Shi/Kbe mice. 238 89

The NOD mouse is a model of human juvenile type I diabetes mellitus. As in humans and in the BB rat model, the development of diabetes in NOD mice is accompanied by evident manifestations of cell-mediated and humoral autoimmunity. Beside autoantibodies directed at putative islet cell antigens, NOD sera contain antibodies with specificity for lymphocyte cell-surface determinants. Here we demonstrate that these anti-lymphocyte antibodies have the same characteristics of target cell specificity, of isotype, and of temperature reactivity, as do natural thymocytotoxic autoantibodies (NTA) from lupic NZB mice, or from mice undergoing polyclonal B cell activation. We also demonstrate that the thymocytotoxic activity of NOD sera is not due to cross-reactive anti-insulin antibodies. Biochemical characterization of the determinants recognized by these anti-lymphocyte antibodies reveals two membrane-associated proteins of 28 and 33 kD, partially similar to the two peptides recognized by NTA from NZB mice (30 and 33 kD). Altogether, these results suggest that NOD mice develop manifestations of polyclonal B cell activation similar to those observed in lupus-prone mice. The relationship of these anomalies with the organ-specific pancreatic disease remains to be properly evaluated.
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PMID:Natural thymocytotoxic autoantibodies in non-obese diabetic (NOD) mice: characterization and fine specificity. 239 10

The role of tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of autoimmune diabetes mellitus was tested in the nonobese mouse (NOD) model system. The effects of TNF-alpha were assessed on three levels: (i) insulitis development, (ii) development of overt diabetes, (iii) adoptive transfer of diabetes by splenic lymphocytes. Spontaneous diabetes mellitus was blocked in NOD mice by long-term treatment with recombinant TNF-alpha. Treatment with TNF-alpha caused a significant reduction in the lymphocytic infiltration associated with the destruction of the insulin-producing beta cells. Class II major histocompatibility complex Ia expression by islet cells was not up-regulated by TNF-alpha. Moreover, TNF-alpha was able to suppress the induction of diabetes in adoptive transfer of lymphocytes from diabetic female mice to young nondiabetic male NOD mice. These activities of TNF-alpha were shared by interleukin 1 alpha in this system. These studies have implications for the pathogenesis and therapy of autoimmune diabetes mellitus.
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PMID:Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): similarities between TNF-alpha and interleukin 1. 240

Insulin-dependent diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas. The results described here indicate that a beta-cell target antigen in non-obese diabetic (NOD/Lt) mice is a molecule cross-reactive with the 65-kDa heat shock protein (hsp65) of Mycobacterium tuberculosis. The onset of beta-cell destruction is associated with the spontaneous development of anti-hsp65 T lymphocytes. Subsequently hsp65 cross-reactive antigen becomes detectable in the sera of the prediabetic mice and some weeks later anti-hsp65 antibodies, anti-insulin antibodies, and anti-idiotypic antibodies to insulin antibodies become detectable. The hsp65-cross-reactive antigen, the autoantibodies, and the T-cell reactivity then decline with the development of overt insulin-dependent diabetes. The importance of hsp65 in the pathogenesis of insulin-dependent diabetes was confirmed by the ability of clones of anti-hsp65 T cells to cause insulitis and hyperglycemia in young NOD/Lt mice. Moreover, hsp65 antigen could be used either to induce diabetes or to vaccinate against diabetes, depending on the form of its administration to prediabetic NOD/Lt mice. Other antigens such as the 70-kDa heat shock protein (hsp70) had no effect on the development of diabetes.
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PMID:Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. 240 23


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