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

Type I, insulin-dependent diabetes (IDD) in both man and animals results from a specific autoimmune destruction of the pancreatic beta cells involving both humoral and cellular immune mechanisms. The pathognomonic histologic lesion, termed insulitis, is an inflammatory and immune cell infiltrate of the pancreatic islet cells. While recent histological and flow cytometric analyses have identified the cell composition of the infiltrate, the presence of a cell population may not reflect the functional reactivities important for beta cell destruction. In the present study, we have investigated the possible functional reactivities of islet-infiltrating mononuclear cell populations by measuring increased cytokine mRNA usage. Results indicate that 1) cytokine mRNA profiles exhibited by islet-infiltrating cells of female and male NOD mice were quite similar with the exception of IL-6 expression and the marked differences in the levels of IL-2 receptor and IL-1 alpha mRNA, 2) CD4+ T lymphocytes expressed IL-4, presumably IL-5, and occasionally IL-10 mRNA but no detectable IL-2 mRNA, 3) CD8+ T lymphocytes exhibited TNF-beta, perforin and high levels of IFN-gamma, and 4) IL-7 was expressed in the islet at very high levels. These findings, together with our earlier flow cytometric analyses of the islet-infiltrating cells, have permitted construction of a detailed model for the natural history of autoimmune diabetes. Interestingly, this model, based on a TH2- and not a TH1-mediated scheme, questions the more popular concepts currently thought to form the bases of the autoimmune reactions underlying IDD.
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PMID:Insulin-dependent diabetes in the NOD mouse model. II. Beta cell destruction in autoimmune diabetes is a TH2 and not a TH1 mediated event. 810 89

The autoimmune process leading to the destruction of pancreatic beta-cells is mediated by T lymphocytes. Peripheral T cells from subjects with preclinical and clinical type I diabetes respond weakly in vitro to lectin stimulation. We, therefore, investigated in a group of newly diagnosed diabetic patients the presence of a defect in the signal transduction pathway of the T cell receptor (TcR)/CD3 complex. Following stimulation with anti-CD3-coupled beads, the proliferative response in diabetic T cells was significantly decreased in comparison with that from normal T cells. Interestingly, addition of either recombinant interleukin (IL)-2 or phorbol 12-myristate 13-acetate to the cell culture was able to completely restore impaired anti-CD3-induced proliferation in diabetic T cells, suggesting the presence of a defect through the TcR/CD3 pathway, located upstream of protein kinase C (PKC) activation and resulting in low IL-2 production and proliferation. Intracellular Ca2+ measurements by Fluo-3 labeling and flow cytometry analysis on diabetic and control T cells after anti-CD3 stimulation gave comparable results, indicating that this defect does not involve events leading to intracellular Ca2+ mobilization. In contrast, anti-CD3 stimulation of diabetic T cells resulted in a marked impairment of PKC translocation and CD69 antigen expression, as assessed by peptide substrate phosphorylation and by flow cytometry analysis, respectively. Taken together, our data clearly show the presence in individuals at the onset of the disease of an in vitro defect in the signal transduction pathway of the TcR/CD3 complex, resulting in ineffective PKC activation which is not able to induce normal IL-2 production and proliferation of diabetic T cells.
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PMID:Defective T cell receptor/CD3 complex signaling in human type I diabetes. 814 68

It has previously been shown that the administration of cyclosporine A to newborn mice results in the development of autoimmunity later in life. It has been proposed that the neonatal administration of cyclosporine A results in altered thymic selection or inhibition of the development of suppressor cells. In the present study, treatment of day 3 thymectomized C3H/HeN mice with cyclosporine A (20 mg/kg/day) for 9 d post surgery increased the prevalence of antigastric autoantibodies. In contrast, the administration of IL-2 (300-600 Units/g/day) for 7 days after thymectomy inhibited the development of antigastric antibodies. We hypothesize that CsA may act by causing transient lymphokine abnormalities in the extrathymic environment during the first few weeks of life which lead to the development of antigastric antibodies. In contrast to the inhibition of development of antigastric antibodies, the administration of a similar course of IL-2 produced only a transient suppression of diabetes in NOD mice. These results and other data suggest that diabetes in NOD mice is probably due to a different immunologic defect.
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PMID:Post-thymectomy organ-specific autoimmunity: enhancement by cyclosporine A and inhibition by IL-2. 821 31

Beginning at the time of insulitis (7 wk of age), CD4+ and CD8+ mature thymocytes from nonobese diabetic (NOD) mice exhibit a proliferative unresponsiveness in vitro after T cell receptor (TCR) crosslinking. This unresponsiveness does not result from either insulitis or thymic involution and is long lasting, i.e., persists until diabetes onset (24 wk of age). We previously proposed that it represents a form of thymic T cell anergy that predisposes to diabetes onset. This hypothesis was tested in the present study by further investigating the mechanism responsible for NOD thymic T cell proliferative unresponsiveness and determining whether reversal of this unresponsiveness protects NOD mice from diabetes. Interleukin 4 (IL-4) secretion by thymocytes from > 7-wk-old NOD mice was virtually undetectable after treatment with either anti-TCR alpha/beta, anti-CD3, or Concanavalin A (Con A) compared with those by thymocytes from age- and sex-matched control BALB/c mice stimulated under identical conditions. NOD thymocytes stimulated by anti-TCR alpha/beta or anti-CD3 secreted less IL-2 than did similarly activated BALB/c thymocytes. However, since equivalent levels of IL-3 were secreted by Con A-activated NOD and BALB/c thymocytes, the unresponsiveness of NOD thymic T cells does not appear to be dependent on reduced IL-2 secretion. The surface density and dissociation constant of the high affinity IL-2 receptor of Con A-activated thymocytes from both strains are also similar. The patterns of unresponsiveness and lymphokine secretion seen in anti-TCR/CD3-activated NOD thymic T cells were also observed in activated NOD peripheral spleen T cells. Exogenous recombinant (r)IL-2 only partially reverses NOD thymocyte proliferative unresponsiveness to anti-CD3, and this is mediated by the inability of IL-2 to stimulate a complete IL-4 secretion response. In contrast, exogenous IL-4 reverses the unresponsiveness of both NOD thymic and peripheral T cells completely, and this is associated with the complete restoration of an IL-2 secretion response. Furthermore, the in vivo administration of rIL-4 to prediabetic NOD mice protects them from diabetes. Thus, the ability of rIL-4 to reverse completely the NOD thymic and peripheral T cell proliferative defect in vitro and protect against diabetes in vivo provides further support for a causal relationship between this T cell proliferative unresponsiveness and susceptibility to diabetes in NOD mice.
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PMID:Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. 831 97

Mononuclear cells obtained from a child at the acute presentation of type I diabetes were stimulated in vitro with human insulin followed by IL-2 and IL-4. All of the T-cell clones isolated from this stimulation were autoreactive, recognizing autologous B cells in the absence of insulin or other exogenous antigens. Eleven CD4+ clones were studied in detail to identify the class II MHC antigens stimulating these autoreactive cells. The donor was heterozygous for DR3DQw2 and DR4DQw3.2 haplotypes, a combination of alleles with a greatly increased risk for type I diabetes. The clones demonstrated skewed recognition of class II antigens. Three clones appeared to recognize a peptide derived from one class II beta chain (DR beta 1, DR4Dw4) presented by another class II beta chain (DR beta 4, DRw53). Three clones were stimulated by cells expressing DPw4 molecules. Only one clone recognized a product derived from the DR3 haplotype. In contrast to both antigen-specific and autoreactive T-cell clones derived from normal individuals, many of the autoreactive T cells isolated from this subject were stimulated by class II molecules other than DR beta 1. The results support the hypothesis that autoreactive T cells recognize autologous peptides in association with MHC and some of these peptides are derived from self MHC molecules.
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PMID:Autoreactive T cells from a type I diabetic recognize multiple class II products. 834 Feb 30

Ten out of 20 (50%) 17-week-old female NOD/WEHI mice developed an acute form of autoimmune diabetes when injected with two large doses of cyclophosphamide (CY), given at 14-day intervals. If these mice were treated under a prophylactic regimen with 2.5 mg/kg body weight per day of the novel immunosuppressant deoxyspergualin (DSP) the onset of diabetes was completely prevented. Moreover, DSP-treated animals showed reduced signs of pancreatic insulitis, had lower percentages of splenic lymphoid cells (SLC) expressing IL-2 receptors and Ly-6C antigens on their surfaces, and these cells released lower amounts of interferon-gamma (IFN) when stimulated in vitro. These data, providing evidence for the capacity of DSP to protect NOD/WEHI mice from experimental autoimmune diabetes and to modulate histo-immunological pathogenic pathways, indicate DSP as a drug of potential interest in the treatment of human insulin-dependent diabetes mellitus.
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PMID:Prevention of cyclophosphamide-induced diabetes in the NOD/WEHI mouse with deoxyspergualin. 842 90

Ciclosporine (CS) caused rapid improvement of anemia and increase of CD 4/8 ratio in two patients with pure red cell aplasia (PRCA). One case was a 45 year old female who were unresponsive to steroids, plasmapheresis and high dose cyclophosphamide, and another was a 61 years old man with diabetes mellitus (DM) without any treatment for PRCA. In both cases hemoglobin increased soon after the initiation of CS and CD 4/8 ratio also rose from 0.80 to 1.47 and 1.78 to 1.98, respectively. There was no side effects to interrupt the course of the therapy. CS seems to inhibit the production of cytokines such as IL-2 and IFN-gamma, and it damages the activated suppressor/cytotoxic T cells. CS is an effective drug for not only refractory cases but the first step therapy for the untreated patients.
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PMID:[Cyclosporin for pure red cell aplasia caused rapid improvement of anemia and increase of CD4/8 ratio]. 849 14

Pregestimil, a hypoallergenic infant formula in which casein hydrolysate replaces protein, protects NOD mice against diabetes, a T-cell-mediated autoimmune disease. Female and cyclosphosphamide (Cy)-treated male NOD mice were used to assess whether a modification of cellular immune mechanisms occurred when animals were fed Pregestimil from weaning to 110 days of life. Insulitis, sialitis and thyroiditis were observed, and the splenic T-cell proliferative response was measured. The ability of splenic T-cells of NOD mice in the Pregestimil group to transfer diabetes adoptively to young irradiated male NOD mice was also assessed. Pregestimil protected female NOD mice against spontaneous diabetes and male NOD mice against acute Cy-induced diabetes. Addition of bovine serum albumin (10%) to the diet did not alter the preventive effect. The Pregestimil diet also lessened insulitis severity in Cy-treated males, though not in females. Sialitis and thyroiditis, observed mainly in females, were not modified by the diets. The TCR-mediated proliferative response of splenocytes tended to increase specifically in Pregestimil-fed and Cy-treated males. Sensitivity to IL-2 was improved. In females, the TCR-mediated proliferative response and the ability of T cells to transfer diabetes adoptively were unchanged. It is concluded that the protective effect of Pregestimil against diabetes in NOD mice cannot be explained by major changes in peripheral immune response.
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PMID:Dietary protection against diabetes in NOD mice: lack of a major change in the immune system. 852 61

Inflammatory cytokines, particularly those produced by Th1 type lymphocytes, are hypothesized to play a major role in the pathogenesis of autoimmune diseases. The present studies investigated this hypothesis in the BB rat. Diabetes-prone (DP) BB rats develop spontaneous hyperglycemia and thyroiditis. Coisogenic diabetes-resistant (DR) BB rats do not develop either disorder spontaneously, but both diseases are induced by depletion of RT6+ T cells. Reverse transcriptase-PCR was used to measure mRNA encoding type 1 and type 2 cytokines. In both DP and RT6-depleted DR rats, IFN-gamma mRNA was present in islets before and during disease onset. IL-2 and IL-4 mRNAs were minimal or undetectable in infiltrated islets but present in activated peripheral T cells. IL-10 mRNA was present at low abundance in infiltrating T cells. These observations suggested a Th1 type inflammatory response, and consistent with this interpretation, we observed that mRNA encoding the p40 chain of IL-12 was also present before and during disease onset. Similar cytokine mRNA profiles were observed in the thyroids of RT6-depleted DR rats and in the islets of DP rats treated with prophylactic parenteral insulin to prevent diabetes. We conclude that IFN-gamma and IL-12 may play a major role in the expression of insulitis and thyroiditis in the BB rat, that Th1 lymphocytes may predominate over Th2 lymphocytes in these inflammatory lesions, and that prevention of diabetes by insulin is not associated with an alteration in the cytokine gene profile of islet infiltrating cells.
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PMID:Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. 855 12

In work performed by a number of laboratories, it has become quite clear that the oral administration of autoantigens exerts a profoundly suppressive effect on the development and long-term clinical course of autoimmune disease. Specific peptide sequences derived from the autoantigens are similarly suppressive. An interesting sidelight to emerge from specificity studies is that oral administration of a self-protein or peptide sequence (i.e., rat MBP peptide administered to a rat) is markedly less tolerogenic than oral administration of a non-self or even closely related sequence (guinea pig MBP peptide administered to a rat). The dose of oral antigen is now known to play a critical role in determination of the mechanism of oral tolerance, with low doses of antigen causing active suppression with concomitant release of TGFbeta1. Studies outlined here suggest that oral administration of higher antigen doses (e.g., 20 mg MBP to rats or mice) results in deletion of specific antigen-reactive T lymphocytes. This conclusion stems from the fact that injections of IL-2 could not reverse high-dose tolerance while reversing low-dose oral tolerance. Moreover, feeding MBP to MBP-TCR transgenic mice caused trafficking of transgenic cells to the intestine followed by a profound depletion of transgene-positive cells and reduction in proliferative function in all peripheral lymphoid organs. Oral tolerance has proven to be of therapeutic benefit in other animal models of autoimmune disease as well, including uveitis, collagen-induced arthritis, adjuvant arthritis, thyroiditis, myasthenia gravis, and diabetes. Initial human trials in multiple sclerosis, rheumatoid arthritis, and uveitis show promising results.
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PMID:Oral tolerance in experimental autoimmune encephalomyelitis. 861 Sep 75


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