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

Currently, 16 loci that contribute to the development of IDDM in the NOD mouse have been mapped by linkage analysis. To fine map these loci, we used congenic mapping. Using this approach, we localized the Idd3 locus to a 0.35-cM interval on chromosome 3 containing the Il2 gene. Segregation analysis of the known variations within this interval indicated that only one variant, a serine-to-proline substitution at position 6 of the mature interleukin-2 (IL-2) protein, consistently segregates with IDDM in crosses between NOD and a series of nondiabetic mouse strains. These data, taken together with the immunomodulatory role of IL-2, provide circumstantial evidence in support of the hypothesis that Idd3 is an allelic variation of the Il2 gene, or a variant in strong linkage disequilibrium.
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PMID:Mapping of the IDDM locus Idd3 to a 0.35-cM interval containing the interleukin-2 gene. 907 13

We have utilized the NOD islet beta-cell line NIT-1 to monitor beta-cell specific autoantibodies and to investigate the modulation of IDDM in NOD mice by NIT-1 membrane associated antigens. The sera from diabetic but not from pre-diabetic or protected NOD mice strongly stained NIT-1 cells in FACS analysis. The cell surface antigens on NIT-1 cells were trypsin-sensitive. NIT-1 cells could not be stained by anti-mouse GAD67 antibody; however, we could demonstrate the presence of GAD65 and GAD67 mRNA by RT-PCR. Longitudinal analysis of anti-NIT-1 antibodies showed that these antibodies were present in the neonates but disappeared after weaning. Sonicated NIT-1 cell membrane preparations protected NOD mice from diabetes when injected intravenously in 5 week old mice. The protection was associated with reduced cytotoxic activity and elevated Th2-like responses as indicated by IgG1 antibodies against the NIT-1 cells. Subcutaneous injection of sonicated NIT-1 membranes or the injection of control red blood cell membranes failed to induce protection. We conclude that NIT-1 cell membranes do not express GAD but contain other antigens that are important in the development and prevention of IDDM. These antigens could be useful for the diagnosis of diabetes by monitoring autoantibody levels and for the modulation of IDDM by immunotherapy.
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PMID:Modulation and detection of IDDM by membrane associated antigens from the islet beta cell line NIT-1. 908 Feb 97

The NOD/Lt mouse, a widely used model of human autoimmune IDDM, was used to establish the mode of beta-cell death responsible for the development of IDDM. Apoptotic cells were present within the islets of Langerhans in hematoxylin and eosin-stained sections of pancreases harvested from 3- to 18-week-old female NOD/Lt mice (a range of 11-50 apoptotic cells per 100 islets). Immunohistochemical localization of insulin to the dying cells confirmed the beta-cell origin of the apoptosis. Although some islets from age-matched control female NOD/scid mice contained apoptotic cells, virtually all of these cells were insulin negative as determined by immunohistochemistry. The small number of apoptotic insulin-positive cells identified in islets from NOD/scid mice (a range of 0-1 apoptotic cells per 100 islets) was not statistically significant, compared with the numbers recorded in NOD/Lt mice. All dying cells showed the morphological changes characteristic of cell death by apoptosis and stained positively with the TUNEL method for end-labeling DNA strand breaks. The maximum mean amount of beta-cell apoptosis occurring in NOD/Lt mice was at week 15 (50 apoptotic cells per 100 islets), which coincided with the earliest onset of diabetes as determined by blood glucose, urine glucose, and pancreatic immunoreactive insulin measurements. While there was no peak incidence of beta-cell apoptosis throughout the time period studied (weeks 3-18), the incidence of apoptosis decreased at week 18, by which time 50% of the animals had overt diabetes. The low levels of beta-cell apoptosis observed is indicative of a gradual deletion of the beta-cell population throughout the extensive preclinical period seen in this model and would be sufficient to account for the beta-cell loss resulting in IDDM. Apoptosis of beta-cells preceded the appearance of T-cells (CD3-positive by immunohistochemistry) in islets. Lymphocytic infiltration of islets (insulitis) was not detected until week 6. The results show that beta-cell apoptosis is responsible for the development of IDDM in the NOD/Lt mouse and that its onset precedes lymphocytic infiltration of the islets.
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PMID:Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. 913 40

Peroxynitrite (ONOO-) is a highly reactive oxidant species produced by the reaction of the free radicals superoxide (O(2).-) and nitric oxide (NO.). Here we report a marked increase in nitrotyrosine (NT), a marker of peroxynitrite, in islet cells from NOD mice developing spontaneous autoimmune diabetes. By using specific antibodies and immunohistochemical methods, we found that NT-positive cells were significantly more frequent in islets from acutely diabetic NOD mice (22 +/- 6%) than in islets from normoglycemic NOD mice (7 +/- 1%) and control BALB/c mice (2 +/- 1%). The NT+ cells in islets were identified to be macrophages and also beta-cells. Most of the beta-cells in islets from acutely diabetic NOD mice were NT+ (73 +/- 8%), whereas significantly fewer beta-cells were NT+ in islets from normoglycemic NOD mice (18 +/- 4%) and BALB/c mice (5 +/- 1%). Also, the percentage of beta-cells in islets from NOD mice (normoglycemic and diabetic) correlated inversely with the frequency of NT+ beta-cells. This study demonstrates for the first time that peroxynitrite, a reaction product of superoxide and nitric oxide, is formed in pancreatic islet beta-cells of NOD mice developing autoimmune diabetes. This suggests that both oxygen and nitrogen free radicals contribute to beta-cell destruction in IDDM via peroxynitrite formation in the islet beta-cells.
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PMID:Development of autoimmune diabetes in NOD mice is associated with the formation of peroxynitrite in pancreatic islet beta-cells. 913 63

Insulin-dependent diabetes mellitus (IDDM) is the result of a T-cell mediated autoimmune beta-cell destruction, which is accompanied by autoantibodies. We analysed the cellular and humoral immune response to insulin and insulin peptides in patients with recent-onset IDDM, IDDM patients treated with insulin, non-diabetic first degree relatives and unrelated control subjects. There were no differences in T-cell reactivity to whole insulin or insulin peptides in general between age-matched groups of IDDM patients, relatives or healthy control subjects. In contrast to investigations in NOD mice, no immunodominant or disease-specific insulin peptide could be identified. Surprisingly, a positive correlation of T-cell responses to insulin with age was noticed (p < 0.005). This resulted in an inverse relation of insulin autoantibodies (IAA) and insulin reactive T-cells (p < 0.001) together with the well-described negative correlation of IAA with age. Interestingly, insulin-treated patients differed from age-matched recent-onset IDDM patients: first, simultaneous immune recognition of insulin with T-cells and IAA was only seen in patients treated for 6 months with insulin; second, insulin-treated patients rarely responded to whole insulin; third, they displayed less determinant spreading, and finally, recognition of multiple insulin peptides was not accompanied by crossreactivity to whole insulin. These distinct observations in insulin-treated IDDM patients, together with the inverse correlation between humoral and cellular responses to insulin, may result from activation or modulation of different T-cell subsets, and may be of relevance to insulin therapy trials, in which selective activation of non-destructive T-cell subsets may be a key to successful intervention.
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PMID:Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects. 916 25

Diabetes is due to an autoimmune cellular immunologic destruction of the pancreatic beta cells. By the use of a chromium release assay and a proliferation assay we have investigated the possible role of beta cell activity for this destruction. Results show that in vitro glucose stimulated pancreatic islet cells are subjects to a slight but significantly higher cellular immunologic destruction by mononuclear spleen cells than unstimulated islet cells. The functional dependency of the islet cell destruction must be a product of both a mononuclear cell dysfunction and a specific islet cell pattern. This is due to the fact that all combinations of mononuclear cells and islet cells from diabetes prone BB rats and non-diabetes prone WF rats tested against each other, results in functional dependent cytotoxicity, except for the assay in which both effector cells and target cells are of WF rat origin. Additional observations indicate, that the diabetes prone BB rat mononuclear cells need previous in vivo activation as only cells from diabetic individuals, and not normoglycemic ones, display the reaction in question. Functional dependent cytotoxicity is validated in an other IDDM animal model--the NOD mouse. NOD mononuclear cells towards the murine MIN-6 beta cell line results in increased cellular cytotoxicity when the latter is glucose stimulated. Also the proliferative response of BB rat mononuclear cells to whole islets tend to show function dependency.
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PMID:Mononuclear cytotoxicity and proliferation towards glucose stimulated rodent pancreatic islet cells. 918 11

The answer to the question posed by the title (is there a relationship between aberrant Art gene expression and IDDM pathogenesis in NOD mice?) remains elusive. Conclusions are currently based almost entirely upon analysis of mRNA transcript levels rather than on T-cell-specific mono-ADP ribosylation activities. Our unpublished data, as well as data published in abstract form by Dr. L. Chatenoud and colleagues (48) indicate that gene transcription is not impaired in splenic leukocytes of older NOD mice, including those with spontaneous IDDM development. Based upon the limited data showing that there may be reduced expression of Art gene products in the earliest T cell immigrants from the NOD thymus, one would have to surmise that If there is a regulatory defect, it may be in allowing single positive thymic T cells to emigrate before they are fully mature. Therefore, development of anti-Art monoclonal antibody together with further studies regarding functions of mono(ADP-ribosyl)transferase in immunoregulation of different subpopulation of T-cells, may finally resolve the role that altered mono(ADP-ribosyl)transferase activities play in the pathogenesis of IDDM in NOD mice.
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PMID:Mono(ADP-ribosyl)transferase genes and diabetes in NOD mice. Is there a relationship? 919 57

IDDM in the NOD mouse is the result of a chronic autoimmune process. NOD mice are shown to express benign autoimmunity that converts to a state of malignant autoimmunity and the development of IDDM. Young disease-prone NOD mice are in a state of benign autoimmunity that is correlated with a non-destructive response to islet tissue and the preservation of insulin-containing beta-cells. A proportion of mice with benign autoimmunity convert to having malignant autoimmunity. Clinical diabetes is diagnosed approximately 3 weeks from the development of malignant autoimmunity which is correlated with a destructive response to grafted islet tissue and extensive beta-cell destruction. We conclude that the development of clinical disease is correlated with a change in the state of autoimmunity, that is, from benign to malignant autoimmunity.
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PMID:Diabetes results from a late change in the autoimmune response of NOD mice. 921 53

A 52 kDa islet protein has recently been identified as the target of autoantibodies in the NOD mouse model of IDDM and humans with IDDM. However, the presence of T cell immunity against the 52 kDa islet protein in IDDM has not been reported. We report the establishment and characterization of a T cell line (19KW) that reacts to purified 52 kDa islet protein (purified p52) from a subject with IDDM. The purified p52 induced a proliferative response as measured by thymidine incorporation in the 19KW T cell line with a stimulating index of up to 48. The proliferative responses were greater with increasing doses of purified p52 (0.1, 0.5, 2.0, and 6.0 microg/well). No reactivity was found to a liver fraction purified in the same manner as 52 kDa protein, BSA, ovalbumin, extracts of rat muscle, fibroblast, adrenal, or pituitary tissue and to a rat exocrine cell tumor. Irradiated PBMC were required as antigen presenting cells (APC) for 19KW reactivity to the purified p52. The addition of anti-HLA DR or anti-HLA DQ antibodies significantly decreased the islet antigen-induced proliferative response. The addition of antibodies to HLA DP and class I MHC had no effect. Flow cytometric analysis revealed that the majority of T cells expressed CD4 and CD45RO molecules. T cell receptors Vbeta6 and Vbeta5.1 were found on 30 and 14% of the CD3+ (T cells) 19KW cells, respectively. In conclusion, a purified p52-reactive human T cell line predominantly consisting of TCR Vbeta6+ and Vbeta5.1+ cells has been established from a subject with IDDM. Reactivity to the purified p52 is antigen dose-dependent, tissue specific, requires irradiated PBMC as antigen presenting cells, and is HLA DR- and HLA DQ-restricted. T cell lines specifically reactive to p52 may be useful for investigating further the role of this antigen in the pathogenesis of IDDM.
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PMID:Characterization of a human T cell line reactive to a 52 kDa islet protein. 923 2

Insulin dependent (type 1) diabetes in humans is a polygenic, auto-immune disease that is characterized, among other things, by the infiltration of the islets of Langerhans by immune cells (insulite) as well as many serum auto-antibodies (including islet cell antibodies: ICA). The medical goal is to diagnose the condition at a sub-clinical stage and then to prevent the disease from developing. Spontaneous diabetic rodent models, in particular the NOD mouse and BB rat are invaluable to the continuing progress of the work aimed at better understanding the human disease. In addition to these models, the study of type 1 diabetes in larger animals, having a longer life-span would also be helpful. In dogs and cats, certain minor kinds of diabetes appear to be of type 1. The classification of diabetes types in carnivores remains poorly defined, however, epidemiological, genetic and metabolic studies are required before these diabetes can be used as operational models for the human pathology. Even if the classification of these diseases is clarified, the ethical and social considerations involved with the use of companion animals, will limit the use of these animals as models for spontaneous diabetes. The selection of a specific line of diabetic dogs should perhaps be considered.
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PMID:[Spontaneous animal models for insulin-dependent diabetes (type 1 diabetes)]. 927 84


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