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

Diabetes-prone BB rats spontaneously develop type 1 diabetes due to a T-cell-dependent destruction of insulin-producing beta-islet cells. A number of T-cell abnormalities including lymphopenia, poor cell-mediated responsiveness to alloantigen, and an absence of an RT6+ T-cell subset are associated with disease susceptibility. Our previous studies have implicated the thymic antigen-presenting cell in influencing disease potential and responsiveness to alloantigen. Since this cell type is also known to influence T-cell receptor expression in developing thymocytes, we examined the thymic and peripheral T-cell receptor beta chain variable region repertoire in diabetes-prone and diabetes-resistant rats. Our findings indicate that animals susceptible to diabetes induction have a characteristic and limited peripheral beta chain variable region repertoire that differs markedly from that expressed in the thymus.
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PMID:Identification of a limited T-cell receptor beta chain variable region repertoire associated with diabetes in the BB rat. 165 91

Insulin-dependent (Type 1) diabetes mellitus is recognized as an autoimmune disease and islet-cell antibody (ICA) is present in the majority of patients at diagnosis. ICA labels both beta and alpha cells and is believed to be directed against a glycolipid. In this study we examine the presence of sulphatide (3'-sulphogalactosylceramide) or closely related structures (sulpholactosylceramide and seminolipid) in islet cells by means of a monoclonal antibody, Sulph I. Histological examination of pancreatic tissue from Lewis and BB rats, and BALB/c and NOD mice showed a pronounced labelling of the islets of Langerhans with Sulph I. No staining of the exocrine pancreatic tissue, the heart, the liver, the adrenals, the thymus, the spleen or lymph nodes was seen, but staining of some tubular cells and glomerular cells in the kidney as well as of myelin in nerve cells was found. Cytological examination of isolated Lewis islet cells and their cell subpopulations, separated using a fluorescence-activated cell sorter (FACS), showed positive surface labelling of 97.3 +/- 2.2% (SD) of the beta cells and 84.4 +/- 3.0% of the non-beta cells. Thus, the epitope on the glycolipid sulphatide or closely related structures is--with the exception of neural and certain kidney tissue--specifically present in islet cells. Furthermore, the staining pattern of the antibody used, Sulph I, was equivalent to that of ICA.
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PMID:Pancreatic islet-cell epitope recognized by an anti-sulphatide monoclonal antibody. 172 82

Insulin-dependent diabetes mellitus (IDDM) is viewed as a thymus-dependent autoimmune disease, although the specific beta-cell autoantigen or autoantigens remain unknown. The recent identification of the beta-cell 64K antigen as the enzyme glutamic acid decarboxylase (GAD) permits investigation of GAD as a candidate for the autoantigen associated with beta-cell destruction, mediated by T-lymphocytes, in susceptible individuals. In this study, we describe the isolation of GAD-specific T-lymphocyte lines from BB rats, an animal model of IDDM. GAD (Escherichia coli) was inoculated into the footpads of diabetes-resistant BB rats, and after 10 days, a popliteal lymph node cell culture suspension was prepared. GAD-specific T lymphocytes were obtained by culture with interleukin 2 and repeated stimulation with GAD in the presence of BB rat thymic antigen-presenting cells. Four stable, CD4+, MHC (RT1u)-restricted T-lymphocyte lines were isolated. They proliferate selectively in the presence of GAD and secrete interleukin 2 and interferon-gamma. T-lymphocyte lines such as these could be important in the definition of pathogenetic epitopes associated with GAD.
Diabetes 1992 Jan
PMID:T-lymphocyte lines specific for glutamic acid decarboxylase (GAD) the 64K beta-cell antigen of IDDM. 172 31

The objective of this study was to determine whether the intrathymic injection of islets can prevent the development of diabetes in BB/Wor rats. Evidence suggests that a failure to induce islet thymic tolerance may be an etiological factor in the development of the disease. It was theorized that the introduction of islets into the thymus might directly induce islet tolerance and thus prevent disease. Islets from diabetes-resistant BB/Wor rats were injected into the thymuses of 23 young diabetes-prone BB/Wor rats; 25 sham-operated animals served as controls. Results showed that 22 of the 25 control rats became diabetic while only 8 of the 23 experimental rats became diabetic (P less than 0.0002). The specific lysis of islet cells by spleen cells from nondiabetic experimental and control rats was comparable and less than the lysis induced by spleen cells from diabetic rats. These data demonstrate that the intrathymic injection of islets into diabetes-prone BB/Wor rats is an effective method for preventing the development of autoimmune type I diabetes.
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PMID:Prevention of diabetes in BB/Wor rats by intrathymic islet injection. 173 41

Besides the thymus-dependent immune system, growing evidence suggests that the functional state of the beta cell plays a role in the pathogenesis of Type 1 (insulin-dependent) diabetes. Increased incidence of diabetes has been described after increased insulin production and vice versa, and actual hyperinsulinemia has been observed in relation to the diabetogenesis. Prophylactic insulin treatment and intensive insulin therapy at diagnosis are discussed. The studies referred to are mostly animal model investigations of BB rats and NOD mice and-to a lesser degree- of streptozotocin- and encephalomyocarditis-virus-induced diabetes. Also human evidence exists, but naturally of a more sporadic character. Three possible mechanisms behind the beta cell sensitivity as a function of their activity are suggested: increased antigen expression (including both gangliosides and proteins) in beta cells with high activity which could activate the destruction caused by the immune system, and increased susceptibility to the toxicity of interleukins and to diabetogenic agents. With respect to developing preventive treatment the described research area may turn out to be very important. Further studies both in animal models and in humans are awaited.
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PMID:The functional state of the beta cells in the pathogenesis of insulin-dependent diabetes mellitus. 174 24

In nonobese diabetic (NOD) mice, T cells play a major role in mediating autoimmunity against pancreatic islet beta-cells. We and others previously reported that age-related alterations in the thymic and peripheral T cell repertoire and function occur in prediabetic NOD mice. To study the mechanism responsible for these T cell alterations, we examined whether a defect exists in the thymus of NOD mice at the level of TCR-mediated signaling after activation by Con A and anti-CD3. We found that thymocytes from NOD mice respond weakly to Con A- and anti-CD3-induced proliferation, compared with thymocytes from control BALB/c, BALB.B, (BALB.B x BALB.K)F1, C57BL/6, and nonobese non-diabetic mice. This defect correlates with the onset of insulitis, because it can be detected at 7 to 8 weeks of age, whereas younger mice displayed a normal T cell responsiveness. Thymic T cells from (NOD x BALB/c)F1 mice, which are insulitis- and diabetes-free, exhibit an intermediate stage of unresponsiveness. This T cell defect is not due to a difference in the level of CD3 and IL-2R expression by NOD and BALB/c thymocytes, and both NOD CD4+ CD8- and CD4- CD8+ mature thymic T cells respond poorly to Con A. BALB/c but not NOD thymic T cells respond to Con A in the presence of either BALB/c or NOD thymic APC, suggesting that the thymic T cell defect in NOD mice is intrinsic to NOD thymic T cells and is not due to an inability of NOD APC to provide a costimulatory signal. The defect can be partially reversed by the addition of rIL-2 to NOD thymocytes. To determine whether a defect in signal transduction mediates this NOD thymic T cell unresponsiveness, we tested whether these cells elevate their intracellular free Ca2+ ion concentration in response to Con A. An equivalent Con A-induced increase in Ca2+ ion concentration in both NOD and BALB/c thymocytes was observed, suggesting a normal coupling between the CD3 complex and phospholipase C in NOD thymocytes. In contrast to their low proliferative response to Con A or anti-CD3, NOD thymocytes respond normally (i.e., as do BALB/c thymocytes) to the combinations of PMA plus the Ca2+ ionophore ionomycin and PMA plus Con A but weakly to Con A plus ionomycin. Our data suggest that the age-related NOD thymocyte unresponsiveness to Con A and anti-CD3 results from a defect in the signaling pathway of T cell activation that occurs upstream of protein kinase C activation.
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PMID:Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice. Evidence for thymic T cell anergy that correlates with the onset of insulitis. 182 15

Single administration of streptozotocin at a dose of 200 mg/kg into mice males of the C57BL/KsJY db/m strain induced severe form of insulin-dependent diabetes within the earlier periods as compared with fractional injection of the drug (40 mg/kg daily within 5 days). Streptozotocin-induced diabetes, developed after single administration of the drug, caused pronounced destructions in lymphoid tissue, primarily in thymus as content of DNA was drastically decreased in the tissue and level of DNA breakdown products was increased. The lympholytic effect of streptozotocin was less distinct after fractional administration.
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PMID:[Study of diabetogenic and lympholytic effects during single and fractional administration of streptozotocin to mice of the mutant strain C57BL/KsIY-db/m]. 183 Apr 35

The spontaneously diabetic BB (BBd) rat displays marked T lymphopenia. The present study was designed to investigate whether the immunodeficiency in this animal may be associated with deficiency of purine nucleoside phosphorylase (PNP) and possibly adenosine deaminase (ADA). The activities of these two enzymes were measured in lymphoid and non-lymphoid cells from both non-diabetes-prone (BBn) and BBd rats as well as from streptozotocin-induced diabetic (STZ) BBn rats. There were no significant differences between BBn and BBd rats in ADA activities in thymocytes, skeletal muscle or brain. However, ADA activity was increased (P less than 0.01) by 50% in BBd mesenteric lymph node lymphocytes and splenocytes as compared with BBn cells, but was not altered in cells from STZ-BBn rats. On the other hand, the PNP activity in BBd thymocytes was only 61% (P less than 0.01) of that observed in BBn cells. This PNP deficiency was not the consequence of diabetes per se, as its activity was normal in thymocytes from STZ-BBn rats. There were no significant differences in PNP activities between BBn and BBd rats in all other cell types examined. The diabetic BB rat may be a novel source of PNP-deficient thymocytes (mainly immature T cells) for studying biochemical mechanisms of immunodeficiency in association with decreased PNP activity. The findings also raise the question of whether a causal relationship exists between PNP deficiency and the recently demonstrated abnormality in T cell maturation in the thymus of the BBd rat.
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PMID:Deficiency of purine nucleoside phosphorylase activity in thymocytes from the immunodeficient diabetic BB rat. 183 79

Mice homozygous for the mutation "severe combined immune deficiency" (C.B17-scid/scid) lack functional T and B lymphocytes and readily accept tumor xenografts. Partial lymphohemopoietic scid/human and mouse/rat chimeras have been described, but complete chimerization with thymic engraftment and generation of donor-origin thymocytes has not been achieved. We now report that low-dose irradiation permits the engraftment of BB rat fetal liver stem cells in scid recipients. We observed that BB rat fetal liver cells injected into irradiated scid mice establish a rat hemopoietic system in the scid mouse bone marrow and populate the scid mouse thymus. These stem cells generated rat-origin thymocytes that migrated to the scid mouse spleen, a peripheral lymphoid organ. Finally, we found that xenogeneic chimeras created using fetal liver cells from the abnormal (lymphopenic, diabetes prone) subline of BB rats recapitulated both the quantitative and phenotypic abnormalities of the donor rat. Xenogeneic lymphohemopoietic chimeras established in scid mice may provide a powerful new tool in the study of immune system development and autoimmunity.
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PMID:Recapitulation of normal and abnormal BB rat immune system development in scid mouse/rat lymphohemopoietic chimeras. 186 81

Diabetes is a T cell-mediated process in NOD/Lt mice, with a major genetically recessive component of susceptibility linked to homozygous expression of the unique H-2g7 MHC haplotype. Heterozygous expression of the H-2nb1 haplotype derived from the NON/Lt strain confers diabetes resistance both in (NOD x NON)F1 hybrids and in NOD mice congenic for the H-2nb1 haplotype. However, diabetes resistance is abrogated in F1 hybrids by NOD/Lt bone marrow reconstitution. To establish whether the generation of beta cell autoreactive T cells from NOD/Lt bone marrow-derived precursors required at least heterozygous expression of the H-2g7 haplotype on thymic epithelium, adolescent thymectomized (NOD x NON)F1 mice were implanted with neonatal NON/Lt thymus grafts before lethal radiation and reconstitution with NOD/Lt bone marrow. Peripheral T cells maturing through this ectopic thymic implant exclusively expressed the NOD H-2g7 haplotype and were tolerant to H-2nb1 skin grafts. Nevertheless, diabetes developed in 32% of the NON/Lt thymus-grafted chimeras vs 38% of the sham-thymectomized NOD bone marrow chimeras. Thus, homozygous expression of the diabetes-resistant H-2nb1 haplotype on thymic epithelium failed to block development of a diabetogenic T cell repertoire. To examine if expression of H-2nb1 on hemopoietically derived APC could alter the diabetogenic potential of NOD/Lt marrow, diabetes-resistant NOD.NON-H-2nb1 congenic mice were mated with NOD/Lt mice to produce NOD-H-2g7/H-2nb1 heterozygous recipients. These were lethally irradiated and reconstituted with either NOD/Lt marrow alone, NOD.H-2nb1 homozygous congenic marrow alone, or a 1:1 mixture of the two marrow populations. By 25 wk of age, all of the MHC heterozygous recipients of NOD.NON-H-2nb1 marrow remained diabetes-free whereas 75% of the MHC heterozygous recipients of NOD/Lt marrow developed diabetes. A striking decrease in diabetes was observed when T cell precursors derived from NOD/Lt marrow interacted with H-2nb1 gene products on hemopoietically derived APC, inasmuch as only 7% of the MHC heterozygous recipients reconstituted with a 1:1 mixture of NOD/Lt and NOD.NON-H-2nb1 marrow developed diabetes. Peripheral leukocytes in all reconstitution classes expressed the MHC phenotype(s) of the marrow donor(s). Skin grafting confirmed that all reconstitution classes of MHC heterozygous recipients were tolerant to the H-2nb1 haplotype.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hemopoietic origin, but not on thymic epithelium. 186 20


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