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

Diabetes-prone (DP) BB rats develop spontaneous autoimmune diabetes mellitus in the context of multiple abnormalities of humoral and cellular immunity. Diabetes-resistant (DR) BB rats have phenotypically normal immune systems and rarely become spontaneously hyperglycemic, but can be rendered diabetic by in vivo immune elimination of T cells that express the RT6 surface alloantigen. To determine if humoral factors in these animals influence beta-cell function, we studied the effect of BB rat plasma on glucose-induced insulin secretion from the isolated perfused rat pancreas. We found that plasma dialyzed to remove molecules less than 14 kD from nondiabetic DR and DP BB rats significantly enhanced total insulin secretion [4806 +/- 711 ng (+/- SEM; n = 6) and 4968 +/- 1235 ng (n = 7), respectively] from perfused pancreata when compared with the effects of either plasma from Wistar-Furth rats (2585 +/- 336 ng; n = 9) or medium containing no plasma (1862 +/- 92 ng; n = 38). The presence of chemically induced diabetes was also associated with enhanced insulin secretion [3276 +/- 414 ng (n = 8) using alloxan and 3956 +/- 470 ng (n = 7) using streptozocin], but the greatest degree of enhancement was observed with plasma from spontaneously diabetic BB rats (6521 +/- 751 ng; n = 17). The enhancement of insulin secretion by BB rat plasma, both diabetic and nondiabetic (DR and DP), was characterized by preservation of first and second phase hormone release. Heat inactivation of acutely diabetic BB rat plasma did not affect its ability to stimulate insulin secretion. We conclude that the plasma of BB rats, both before and after the onset of autoimmune diabetes mellitus, contains a factor other than complement of greater than or equal to 14 kD that enhances insulin secretion in vitro from the isolated perfused pancreas.
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PMID:Plasma from BB/Wor rats increases insulin secretion by perfused rat pancreas. 240 44

Lymphoid irradiation is known to prevent spontaneous autoimmune diabetes in susceptible BB rats. The present studies investigated further the effects of radiation in diabetes prone (DP) and resistant (DR) BB/Wor rats, and histocompatible Yoshida (YOS) rats. Single doses of total body gamma irradiation (125-600 rads) induced diabetes within 22-44 days in 20 of 102 (20%) 30 day old DR rats, less than 1% of which develop the disease. Radiation was also associated with (1) a reduction in the ratio of W3/25+ to OX8+ peripheral blood lymphocytes within 2 weeks, and (2) a decreased percentage of lymph node cells expressing the RT6.1 surface alloantigen 3-4 weeks after treatment. Similar doses of irradiation did not alter the frequency or age at onset of diabetes in DP rats, and did not induce diabetes in YOS rats. When a single dose of 250 or 500 rads of gamma irradiation was followed by injection of mitogen activated spleen cells from acutely diabetic rats to adoptively transfer diabetes, 16 of 19 (84%) DR and 8 of 14 (57%) YOS rats became diabetic. Long term exposure to ultraviolet irradiation (UVB) did not alter the frequency or age at onset of diabetes in either DP or DR rats. We conclude that there may exist a population of regulatory cells relatively sensitive to gamma irradiation that play a role in determining the susceptibility of rats to autoimmune diabetes mellitus.
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PMID:Effects of irradiation on diabetes in the BB/Wor rat. 249 39

Diabetes prone BB (DP BB) rats are known to develop insulin dependent diabetes mellitus. In addition, a number of other immune abnormalities have been observed, like severe T lymphopenia, lack of CD8+ T cells, and lack of RT6+ T cells. Here we report double-labelling studies of lymph node T cells using MRC OX-32 (CD45R), and demonstrate that this T cell subset is absent in young adult DP BB rats. Since both RT6 and MRC OX-32 antigens are only expressed by mature peripheral T cells, it is tempting to speculate that the peripheral T cell pool of DP BB rats consists only of immature peripheral T cells, i.e. recent thymic emigrants.
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PMID:Peripheral T cells in diabetes prone (DP) BB rats are CD45R-negative. 253 58

In an outcross between a diabetic BB/H rat and a healthy Long Evans Hooded rat, the segregation of the RT6 gene was studied in the 207 F2 animals to look for linkage with diabetes or lymphopenia. The recessive gene, albino (c), was used as a marker for the RT6 gene because of the close proximity of these two genes on chromosome 1. Though most of the albino F2 rats should have been homozygous for the BB RT6 gene, we found no increase in the incidence of diabetes or lymphopenia among them when compared to their hooded littermates. Therefore, the RT6 gene was not linked to diabetes or lymphopenia in the BB rat. Moreover, the non-lymphopenic albino rats displayed normal RT6 expression when compared to the normal hooded rats showing that the RT6 gene from the BB/H grandfather was not defective. Any alteration in lymphocyte composition which could be specifically related to diabetes was studied by measuring all F2 rats for the major lymphocyte subsets including the RT6+ subset. We found that the typical pattern of lymphopenia described in diabetic BB rats was displayed by both diabetic and non-diabetic lymphopenic rats in the F2 generation. Thus, all these lymphocyte abnormalities including the depletion in RT6+ T lymphocytes appeared as a consequence of lymphopenia alone and could not be specifically related to diabetes.
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PMID:The gene for the T lymphocyte alloantigen, RT6, is not linked to either diabetes or lymphopenia and is not defective in the BB rat. 258 21

Diabetes-prone BB/Wor (DP) rats lack the RT6+ peripheral T cell subset whereas diabetes-resistant BB/Wor rats have normal numbers of RT6+ T cells. Lymphocyte transfusion experiments and in vivo depletion studies have demonstrated that RT6+ T cells have an important regulatory role in the pathogenesis of insulin-dependent diabetes mellitus in BB/Wor rats. In the present study, the results of genetic complementation studies indicate that the DP rat contains an intact RT6 gene, but fails to express the RT6.1 alloantigen in the functional absence of an accessory factor (provided by RT6+ cells). At the cellular level, irradiation chimeras demonstrate that the absence of RT6+ T cells in DP rats is due to an intrinsic defect that results in abnormal development and/or differentiation of prothymocytes into RT6+ T cells. The inability of DP prothymocytes to generate RT6+ T cells is not due to serum autoantibodies, lack of accessory cells, or to the presence of inhibitory cells. Inasmuch as DP bone marrow can transfer the susceptibility for diabetes to irradiated recipients, our present results suggest that an important predisposing factor for insulin-dependent diabetes mellitus in DP rats is the inability of DP prothymocytes to generate RT6+ T cells.
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PMID:Absence of RT6+ T cells in diabetes-prone biobreeding/Worcester rats is due to genetic and cell developmental defects. 305

BB rats are prone to develop an autoimmune form of insulin-dependent diabetes mellitus (IDDM) and thyroiditis. Development of autoimmunity is thymus dependent. Previous studies have shown that BB rats lack a population of T cells bearing the RT6 antigen and have very low numbers of suppressor/cytotoxic T cells. In this study, we confirm that BB rats have decreased numbers of phenotypic T suppressor/cytotoxic (Ts/c) cells (OX19+, OX8+ cells) in their lymphoid organs. Moreover, we find that the phenotypic Ts/c cells of BB rats lack apparent cytotoxic activity. These T cells fail to kill allogeneic target cells in a cell-mediated lympholysis assay and fail to generate lectin-dependent cytotoxicity. The addition of interleukin 2, gamma-interferon, and other lymphokines to cultures of BB T cells does not induce functional cytotoxic T lymphocytes. We find that the activated T cells of newly diabetic rats are incapable of killing major-histocompatibility-complex-matched islet cells, despite the ability of these cells to cause IDDM in passive transfer experiments. We conclude that autoimmune disease occurs in BB rats in the absence of functional cytotoxic T cells.
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PMID:Autoimmunity-prone BB rats lack functional cytotoxic T cells. 313 Oct 22

To investigate the role of RT6+ T cells in the pathogenesis of diabetes in BB/W rats, we treated animals from the diabetes-resistant (DR) subline with anti-RT6.1 lymphocytotoxic mAb. This depleted greater than 95% of peripheral RT6+ T cells but did not substantially reduce levels of circulating T cells or the in vitro response of spleen cells to mitogen. Treatment of 30-d-old DR BB/W rats in this way: induced insulitis and diabetes, rendered nondiabetic RT6-depleted DR rats susceptible to the adoptive transfer of diabetes by spleen cells from acutely diabetic BB/W rats, and yielded DR spleen cell populations capable of the adoptive transfer of diabetes to diabetes-prone (DP) or DR recipients. Treatment of DR rats beginning at 60 d of age failed to produce these effects. These results suggest that both susceptibility and resistance to diabetes in the BB/W rat are in part regulated by the RT6+ T cell subset and provide evidence for the importance of regulatory T lymphocytes in the pathogenesis of autoimmunity and diabetes in BB/W rats.
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PMID:Depletion of RT6.1+ T lymphocytes induces diabetes in resistant biobreeding/Worcester (BB/W) rats. 349 16

We have induced autoimmune insulin-dependent diabetes mellitus (IDDM) in athymic WAG rats by transfusing thymocytes from histocompatible phenotypically normal rats of the DR-BB strain. DR-BB rats rarely develop spontaneous IDDM, but readily become hyperglycemic if depleted in vivo of regulatory T-cells that express the RT6.1 maturational alloantigen. Successful adoptive transfer of IDDM by DR-BB thymocytes required that the athymic recipients be depleted of emerging populations of donor-origin RT6.1+ T-cells. Thymocytes from both normal and RT6-depleted diabetic DR donors were equally capable of transferring autoimmunity. In contrast, thymocytes from normal histocompatible YOS rats failed to transfer IDDM. The autoreactive potential of DR-BB rat thymocytes was minimal from birth to 4 weeks of age and then increased substantially at 8-9 weeks of age. These results demonstrate that the DR-BB rat thymus harbors abnormal cell populations predisposed to autoreactivity. The data localize the developmental defect leading to diabetes in the BB rat to an abnormal intrathymic selection process.
Diabetes 1995 Aug
PMID:DR-BB rat thymus contains thymocyte populations predisposed to autoreactivity. 762 3

T-cells expressing the RT6 surface alloantigen appear to perform important immunoregulatory functions in the rat. Diabetes-prone BB rats lack circulating RT6+ T-cells and spontaneously develop autoimmune diabetes mellitus and thyroiditis. The coisogenic diabetes-resistant BB rat does circulate RT6+ T-cells and is free of disease. Transfusions leading to engraftment of RT6+ T-cells prevent both diabetes and thyroiditis in the diabetes-prone rat. To investigate the absence of this subset in the lymphopenic BB rat, we used both molecular and biochemical procedures and made the following observations: 1) an mRNA encoding RT6 protein is present in diabetes-prone spleen cells; 2) nucleotide sequencing of this transcript reveals an intact coding sequence for the RT6.1 alloantigen; 3) sensitive chemiluminescent assay of diabetes-prone lymph node cell detergent extracts shows that diabetes-prone RT6 mRNA is translated in vivo; 4) quantitatively, diabetes-prone lymph node cells express < or = 10% of the RT6.1 protein found on similar numbers of diabetes-resistant BB cells; and 5) finally, we obtained evidence of an intact phosphatidylinositol linkage of the molecule to the cell surface and successfully immunoprecipitated the phosphatidylinositol-linked protein with DS4.23 monoclonal antibody, indicating that the RT6.1 antigen is correctly processed and folded in diabetes-prone lymph node cells. We conclude that the near total absence of RT6+ T-cells in the diabetes-prone BB rat is unlikely to be because of a defect in RT6 gene expression per se. Defects in RT6 gene regulation or other cellular defects leading to premature cell death in the T-cell lineage, alone or in combination, may instead be responsible.
Diabetes 1993 May
PMID:An RT6a gene is transcribed and translated in lymphopenic diabetes-prone BB rats. 768 89

We describe the induction and prevention of autoimmune insulin dependent diabetes mellitus (IDDM), and its pathological substrate, insulitis, in congenitally athymic nude rats following injections of major histocompatibility complex (MHC) compatible lymph node T cells. The cells capable of adoptive transfer of autoimmunity were obtained from diabetes resistant (DR) BB rats that had been rendered hyperglycemic by in vivo depletion of the RT6+ regulatory T cell subset. We first established that our adoptive transfer assay system is cell dose- and time dependent and therefore amenable to quantitative analysis. It was also observed that both CD4+ and CD8+ T cells are required for efficient transfer of autoimmunity. The data indicate that, as in the NOD mouse, a synergistic interaction between CD4+ and CD8+ T cells is important for beta cell destruction. Finally, we demonstrated that the admixture of equal numbers of lymph node T cells, 60% of which were RT6+, from intact, non-diabetic DR rats prevented the adoptive transfer of IDDM mediated by diabetogenic T cells from RT6-depleted DR-BB rats. We conclude that an equilibrium between autoreactive and regulatory cells determines the expression of autoimmunity in the DR-BB rat and in the adoptive transfer of diabetes in quantitative analytical systems.
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PMID:Adoptive transfer of autoimmune diabetes mellitus to athymic rats: synergy of CD4+ and CD8+ T cells and prevention by RT6+ T cells. 788 38


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