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)

The spontaneous development of diabetes in the Bio-Breeding (BB) rat is an excellent model of human insulin-dependent diabetes mellitus (IDDM). Disease expression is dependent on several genetically determined abnormalities, including specific major histocompatibility complex (MHC) genes. At least one MHC class II locus of the U haplotype is a necessary, but not sufficient, condition for disease expression. The immune system of BB rats is markedly abnormal. There is a striking reduction in the number and function of mature cytotoxic/suppressor T cells, a poor proliferative response to mitogens and in mixed lymphocyte culture, poor interleukin-2 production, and a reduced ability to reject skin allografts. While these immune system abnormalities are closely related to the development of diabetes, the immune recognition and effector mechanisms resulting in islet cell destruction are still poorly understood. The hypothesis that MHC class II induction on pancreatic beta cells serves to target these lymphokines, natural killer (NK) cells, macrophages, etc.) have been implicated in islet cell killing. The incidence of IDDM is reduced by immunosuppressive therapy in both rats and humans, further supporting the role of immune mechanisms in this disease.
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PMID:Immunologic and genetic studies of diabetes in the BB rat. 265 Oct 2

Anti-islet cell-mediated immunity in the Bio-Breeding/Worcester (BB/Wor) rat was studied by measuring the cytotoxic activity of splenic lymphoid cells from diabetes-prone (DP) rats receiving either oral cyclosporine (Cy-A, 10 mg/kg/d) or olive oil vehicle (DP control) from age 40 to 105 d. Splenic cells were incubated with concanavalin A (Con-A) for 16 h, then used as effector cells in cytotoxicity assays with 51Cr labeled cells from a rat islet cell line (RIN) as targets. Lysis of RIN cells (% 51Cr release) by Con-A-activated splenic cells from control DP rats increased from age 40 d (5.4 +/- 1.6%) to 105 d (32.7 +/- 1.8%). This increase was significantly less in Cy-A-treated DP rats (14.5 +/- 3.2%) and remained low at 15 d after stopping Cy-A (14.8 +/- 2.5%). Diabetes developed in control DP rats between 74 and 120 days of age, and in none of the Cy-A-treated DP rats by age 105 d, nor for 15 d after stopping Cy-A. The Con-A-activated splenic cells responsible for lysis of RIN cells also lysed normal rat islet cells and had the functional and phenotypic properties of natural killer (NK) cells. In contrast to the lower Con-A-inducible NK cell cytotoxic activity in Cy-A-treated DP rats, basal NK cell activity and monoclonal antibody-defined NK cell subsets were increased in the Cy-A-treated DP rats. Therefore, Cy-A had inhibited the ability of NK cells to respond to cytotoxic activation despite their increased numbers. To investigate the mechanism(s) of the protective effect of Cy-A, we examined the direct effects of Cy-A in vitro. Cy-A (100 ng/ml) inhibited completely Con-A activation of DP splenic cells cytotoxic to islet cells, and this was accompanied by a similar inhibition of interleukin-2 (IL-2) production. Also Cy-A (300 ng/ml) inhibited partially (approximately 65%) IL-2 activation of DP splenic cells cytotoxic to islet cells. In addition, Cy-A inhibited the cytotoxic effects of DP cells previously activated by Con-A, and 300 ng/ml Cy-A produced a maximum inhibition of 47 +/- 5%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanisms of cyclosporine protection against spontaneous diabetes mellitus in the BB/W or rat. 266 95

Although convincing evidence has been obtained for the imposition of self-tolerance by the intrathymic deletion of self-reactive T cells, the development of tolerance to antigens which are expressed only in the periphery is not so well understood. We have approached this question by creating transgenic mice which carry a class I major histocompatibility complex (MHC) gene (H-2Kb) linked to the rat insulin promoter. Mice expressing the transgene develop diabetes, but do not appear to mount an immune response against the transgene-expressing pancreatic beta-cells, even when the transgene is allogeneic with respect to the endogenous host H-2 antigens. We have now explored the mechanism of this tolerance further. We find that spleen cells from pre-diabetic transgenic (RIP-Kb) mice do not kill targets bearing H-2Kb, whereas thymus cells from the same mice do. The unresponsiveness of these spleen cells can be reversed in vitro by providing recombinant interleukin-2 (rIL-2). In older, diabetic mice, responsiveness develops as the pancreatic beta-cells are lost. Our results point to an extrathymic mechanism of tolerance induction, dependent on the continuous presence of antigen and the lack of IL-2 in the local environment of potentially reactive T cells.
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PMID:Tolerance of class I histocompatibility antigens expressed extrathymically. 278 8

Recombinant interleukin-2 (IL2) was labelled with iodine-123 by a modified chloramine T method. The labelled IL2, which had a high specific activity (100-150 microCi/microgram) and retained its capacity for binding to the IL2 receptor on activated lymphocytes in vitro, was injected intravenously into BB/W diabetes-prone and normal rats. Combined immunoperoxidase staining and autoradiography of organ sections revealed that labelled IL2 bound specifically in vivo to IL2-receptor-positive cells in the spleen of both normal and BB/W rats and to activated lymphocytes infiltrating the pancreas of BB/W rats. The severity of lymphocytic infiltration correlated with the degree of radioactivity in the pancreas of BB/W rats. Time-activity curves, generated over organs of injected rats after gamma camera imaging, confirmed that radioactivity was greater in the pancreas of diabetes-prone than in normal rats. 123I is a suitable isotope for gamma camera imaging, so the intravenous injection of IL2 labelled with iodine-123 may be valuable for the in-vivo visualisation of activated lymphocytes in tissues infiltrated by lymphocytes.
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PMID:Detection of activated lymphocytes in endocrine pancreas of BB/W rats by injection of 123I-interleukin-2: an early sign of type 1 diabetes. 288 34

The efficacy of the diabetogenic drugs streptozotocin and alloxan were evaluated as models for the study of immune defects associated with diabetes. Streptozotocin- or alloxan-treated mice, with a stable hyperglycaemia of 25-33 mmol/l plasma glucose, were severely impaired in their ability to mount antibody forming, mitogenic, or delayed-type hypersensitivity responses in vivo. Treatment of alloxan-diabetic mice with insulin in vivo completely reversed all immune defects, while insulin treatment of streptozotocin-diabetic mice restored immune function to only 70-80% of normal levels. Results obtained by viability measurements and in vitro biological assays of lymphoid function, including proliferation in response to T- and B-cell mitogens, the production of interleukin-2 by T cells, and the production of interleukin-1 by macrophages indicated that direct exposure to alloxan for 48 h (at concentrations less than or equal to 14 mmol/l) had no adverse effects on lymphoid activity, while exposure to streptozotocin was routinely toxic at concentrations greater than or equal to 1 mmol/l. Both alloxan and streptozotocin exhibited strong toxicity in vitro for isolated pancreatic islet cells. Finally, lymphocytes from streptozotocin-diabetic mice, or cells incubated in vitro with streptozotocin, contained numerous chromosomal abnormalities indicative of DNA strand breakage. Such abnormalities were absent in alloxan-diabetic mice and in cells incubated with alloxan in vitro. These results indicate that immune dysfunction associated with streptozotocin is attributable to direct and irreversible impairment of lymphoid cell function and viability. In contrast, immune dysfunction associated with alloxan-diabetes appears to be a consequence of the diabetic state.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of the diabetogenic drugs alloxan and streptozotocin as models for the study of immune defects in diabetic mice. 293 86

In the present study, we investigated the interleukin-2 (IL-2) production and the proliferative responses by peripheral blood mononuclear cells (PBMNC) of 23 children suffering from insulin-dependent diabetes mellitus (IDDM). In addition, the presence of circulating activated T lymphocytes expressing the interleukin-2 receptor (IL-2 R) and HLA-DR antigens was evaluated. The patients were tested at hospital admittance, before starting insulin treatment. Decreased IL-2 production by phytohemagglutinin (PHA)-activated PBMNC of IDDM patients was observed when compared to normal donors. In contrast, the proliferative responses of PBMNC to PHA and Con A were in the normal range. The expression of IL-2 R on patient's lymphocytes was not different from that observed in normal donors, whereas the relative and absolute number of HLA-DR+ T cells was increased. These results confirm the presence in IDDM patients of an imbalanced cellular immune response and demonstrate that the IL-2 deficiency is already present at the diagnosis and is not correlated with insulin administration.
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PMID:Interleukin-2 production and interleukin-2 receptor expression in children with newly diagnosed diabetes. 313 60

Young diabetes prone BB/Wor rats were treated for 4-7 weeks with low dose (1,000 units/week) or high dose (75,000 units/week) recombinant human interleukin-2 (IL-2) and observed through 150 days of age for the development of spontaneous diabetes mellitus. Comparing treated rats with controls, it was found that IL-2 did not affect the cumulative incidence of diabetes, the age at onset of the disease, or peripheral lymphocyte subset numbers. High dose IL-2 administered to diabetes resistant BB/Wor rats also failed to induce the disease.
Diabetes Res 1987 Aug
PMID:Effect of interleukin-2 on diabetes in the BB/Wor rat. 349 82

Human recombinant interleukin-2 (IL-2) was labelled with Iodine-123 using modified Bolton and Hunter method. Separation from free iodine was performed by gel filtration chromatography using a Sephadex G10 column. HPLC analysis of labelled IL-2 showed that 98% of TCA precipitable radioactivity eluted in a single peak. The immunoreactivity of 123I-labelled IL-2 was determined by divert binding using the Fluorescence Activated Cell Sorter (FACS) and by receptor binding assay of IL-2 to activated lymphocytes. To demonstrate in vivo binding to activated lymphocytes, 123I-labelled IL-2 was injected intravenously into a newly diagnosed diabetic BB/Wistar rat. Higher radioactivity was detected in the pancreas and in the lymph nodes of the BB/W rat compared to a normal rat. These preliminary data show that 123I-labelled IL-2 retains its immunoreactivity and capacity to bind to activated lymphocytes both in vitro and in vivo and may be used for in vivo localization of lymphocytic infiltration in Type 1 diabetes.
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PMID:Labelling of interleukin-2 (IL-2) with 123-iodine with retention of its capacity to bind to activated lymphocytes. 349 31

Addition of highly purified human Interleukin-1 to the culture medium of isolated rat islets of Langerhans for 6 days led to 88% inhibition of glucose-induced insulin-release, reduction of islet contents of insulin and glucagon to 31% and 8% respectively, and disintegration of the islets. These effects were dose-dependent and reproducible when using three different Interleukin-1 preparations. Highly purified human Interleukin-2, Lymphotoxin, Leucocyte Migration Inhibitory Factor and Macrophage Migration Inhibitory Factor were ineffective. These findings suggest that Interleukin-1 may play an important role in the molecular mechanisms underlying autoimmune B-cell destruction leading to Type 1 (insulin-dependent) diabetes mellitus.
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PMID:Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. 351 44

Deficient production of interleukin-2 has been reported in Type I diabetes, but its cause has not been elucidated. We therefore measured interleukin-2 production in 27 patients with Type I diabetes, 20 patients with Type II diabetes (6 requiring insulin), 5 monozygotic twin pairs discordant for Type I diabetes, and 10 nondiabetic persons with islet-cell antibodies. Interleukin-2 production was decreased in patients with Type I diabetes as compared with controls (35.8 +/- 2.5 vs. 61.6 +/- 4.6 percent, P less than 0.001). Interleukin-2 production did not differ between patients with Type II diabetes and controls, regardless of whether the patients used insulin. Twins with Type I diabetes had decreased interleukin-2 production as compared with normal controls (33.2 +/- 5.4 vs. 61.6 +/- 4.6 percent, P less than 0.001) and with their nondiabetic twins (33.2 +/- 5.4 vs. 54.5 +/- 3.4 percent, P less than 0.005). Interleukin-2 production in nondiabetic twins and in nondiabetic persons with islet-cell antibodies was normal. There was no correlation between glycosylated hemoglobin levels and interleukin-2 production in any diabetic group. We conclude that patients with Type I diabetes have an acquired defect in interleukin-2 production, whereas patients with Type II diabetes do not, and that this defect is not correlated with an ongoing autoimmune process, with hyperglycemia, or with insulin administration or oral hypoglycemic therapy. Thus, the defect appears to be related to marked beta-cell destruction, although not to the metabolic consequences thereof or the responsible autoimmune process.
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PMID:Acquired defect in interleukin-2 production in patients with type I diabetes mellitus. 353 50


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