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)

T cell activation is dependent upon calcium influx and protein kinase C activation, with subsequent lymphocyte proliferation dependent upon IL-2. Abnormalities in T cell proliferation, including abnormal calcium influx and defective protein kinase C activation, have been identified in aged mice and humans and many autoimmune diseases including diabetes, lupus and scleroderma. Since UCD line 200 chickens, which spontaneously develop a scleroderma-like disease, have both thymic defects and a diminished peripheral blood lymphocyte response to IL-2, we have further investigated T cell function in these birds. Interestingly, line 200 T cells respond poorly in vitro to a variety of diversely acting T cell mitogens including concanavalin A, phytohemagglutinin and anti-chicken CD3 monoclonal antibody. Moreover, they do not respond well even to phorbol myristate acetate in conjunction with ionomycin. Addition of exogenous IL-2-containing supernatant concurrently with mitogenic stimulation also had no significant effect. Analysis of intracellular free calcium demonstrated that the lymphocytes from diseased birds had a reduced influx of calcium (or release for intracellular stores) following stimulation. These data clearly reflect a unique defect in T cell activation associated with avian scleroderma. Analysis of chicken CD3, CD4 and CD8 expression revealed a 39% decrease in peripheral blood CD4+ cells in scleroderma birds, although this decrease was not sufficient to explain the 80-90% decrease observed in proliferation assays and calcium influx. Our data support the hypothesis that avian scleroderma is mediated via abnormal function of lymphocyte co-stimulatory molecules or intracellular calcium regulators.
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PMID:Avian scleroderma: evidence for qualitative and quantitative T cell defects. 138 34

The possible role of interleukin 2(IL-2) in the pathogenesis of multiple low dose streptozotocin (Sz)-induced diabetes in mice was analysed. Spleen cells from diabetic male C57Bl/6 mice showed diminished mitogen-induced IL-2 production as determined by bioassay using the IL-2-dependent T-cell line CTLL-2. In parallel the proliferative response was reduced. Systemic daily administration of human recombinant IL-2 for 3 weeks had dose-dependent effects on the development of hyperglycemia in Sz-treated (5 x 40 mg) mice: while IL-2 at doses of 1 x 2, 1 x 10, 2 x 10 micrograms/kg body weight caused partial suppression of hyperglycemia, higher doses (2 x 20, 2 x 40 micrograms/kg) had an enhancing effect. Treatment with the lowest dose (1 x 1 micrograms/kg) or with a control preparation from bacteria (2 x 10 micrograms/kg) did not significantly alter the course of diabetes. Effects of IL-2 were similar when treatment was started concomitantly with or only after streptozotocin injections. This observation argues against the direct interaction between IL-2 and streptozotocin but suggests modulation of immune reactivity by IL-2. Our findings of decreased mitogen-stimulated IL-2 production by splenic lymphocytes, and the disease-modulating effect of IL-2 in the low-dose streptozotocin diabetes extend our previous observations in spontaneously diabetic BB rats and further support the notion of an involvement of IL-2 in the control of autoimmune diseases.
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PMID:Low dose streptozotocin-induced diabetes in mice: reduced IL-2 production and modulation of streptozotocin-induced hyperglycemia by IL-2. 142 58

Insulin-dependent diabetes mellitus (IDDM) is strikingly similar in the non-obese diabetic (NOD) mouse and humans. In IDDM, the systematic autoimmune destruction of insulin-producing beta cells within the pancreas is dependent on autoreactive T cells. This autoimmune process can be accelerated by transferring spleen cells from diabetic donors into irradiated syngeneic NOD mice. In a previous study we established that interleukin 2 receptor (IL 2R)-bearing cells propagated from pre-diabetic NOD mice promote IDDM. Therefore, we reasoned that specific elimination of IL 2R+ T cells should abort the diabetogenic process. T cell expressing IL 2R can be selectively destroyed with a diphtheria toxin-related IL 2 fusion protein (DAB486-IL-2). We set DAB486-IL-2 the challenging task of preventing fulminant IDDM accelerated by the adoptive transfer of diabetic spleen cells. Eight weeks after the adoptive transfer only 10% and 20% of NOD mice treated with 10 and 5 micrograms/day of DAB486-IL-2, respectively, became diabetic while 100% control mice (vehicle buffer) became diabetic within 5 weeks. A dose of 1 microgram/day of DAB486-IL-2 had no protective effect. Although the protection conferred by DAB486-IL-2 is not permanent, it is maintained for at least 4 weeks following cessation of treatment. Furthermore, even though these NOD mice do eventually become diabetic, the tempo of expression and severity of diabetes, as assessed by the level of hyperglycemia, is dramatically reduced. Although histologic examination of pancreas revealed minimal degree of mononuclear infiltrate within the islets in both groups, the vehicle control mice had fewer islets per section indicating many islets had already been destroyed. In addition, spleen cells from diabetic NOD mice which were pre-treated with DAB486-IL-2 (10 micrograms/day) for 1 week lost their ability to transfer disease. Taken together, these studies strongly support the concept that IL 2R-bearing T cells are essential for the induction of IDDM and suggest that DAB486-IL-2 would be a promising therapeutic approach in the treatment of human IDDM.
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PMID:Interleukin 2 receptor targeted fusion toxin (DAB486-IL-2) treatment blocks diabetogenic autoimmunity in non-obese diabetic mice. 154 15

Pancreatic beta cell destruction in the non-obese diabetic (NOD) mouse is mediated by T lymphocytes and macrophages and accelerated by cyclophosphamide. We purified pancreatic T lymphocytes from the NOD mouse for comparative phenotypic and functional analysis with T lymphocytes from spleen, peripheral blood and regional lymph nodes. Pancreatic T lymphocytes from NOD-Wehi mice, which have an incidence of spontaneous diabetes of less than 5%, had a CD4:CD8 ratio of 1.25 +/- 0.23 compared with 2.44 +/- 0.31 for peripheral blood lymphocytes. After cyclophosphamide, the CD4:CD8 ratio of pancreatic lymphocytes increased to 2.30 +/- 0.24 at day 7. T lymphocytes bearing IL-2 receptors increased two- to three-fold in number and their secretion of GM-CSF/IL-3 and IFN-gamma increased to a maximum on day 7. Pancreatic insulin content and mRNA levels declined sharply between days 10 and 12, at which time the majority of pancreatic T lymphocytes in hyperglycaemic mice were CD8+ (CD4:CD8 ratio 0.63 +/- 0.04 compared to 4.14 +/- 1.05 in peripheral blood). The pancreatic T lymphocyte CD4:CD8 ratio in prediabetic NOD-Lt mice, which have an incidence of spontaneous diabetes of about 60% at 150 days, was similar to that in untreated NOD-Wehi mice, but 25% of their pancreatic CD8 T lymphocytes were IL-2-receptor positive. Thus, significant changes in the phenotype of NOD pancreatic T lymphocytes following cyclophosphamide were not reflected in peripheral blood or spleen T lymphocytes. The earliest change after cyclophosphamide was an increase in activated, predominantly CD4+ T lymphocytes; with the development of beta cell destruction and hyperglycaemia, pancreatic T lymphocytes were, as in human IDDM, predominantly CD8+.
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PMID:Characterization of pancreatic T lymphocytes associated with beta cell destruction in the non-obese diabetic (NOD) mouse. 167 32

We have recently reported that systemic and chronic administration of recombinant tumour necrosis factor alpha (TNF-alpha), as well as streptococcal preparation (OK-432), inhibits development of insulin-dependent diabetes mellitus (IDDM) in NOD mice and BB rats, models of IDDM. In this study we examined whether serum containing endogenous TNF induced by OK-432 injection could inhibit IDDM in NOD mice. Treatment twice a week from 4 weeks of age with OK-432-injected mouse serum, which contained endogenous TNF (75U), but not IL-1, IL-2 and interferon-gamma (IFN-gamma) activity, reduced the intensity of insulitis and significantly inhibited the cumulative incidence of diabetes by 28 weeks of age in NOD mice, as compared with the incidence in non-treated mice (P less than 0.01) and in mice treated with control serum (P less than 0.02). This inhibitory effect of the serum was diminished, although not significantly, by neutralization of serum TNF activity with anti-mouse TNF antibody. In the mice treated with the serum from OK-432-injected mice, Thy-1.2+ or CD8+ spleen cells decreased (P less than 0.01) and surface-Ig+ (S-Ig+) cells increased (P less than 0.05), whereas the proliferative response of spleen cells to concanavalin A (P less than 0.01) and lipopolysaccharide (P less than 0.05) increased. The results indicate that the inhibition by OK-432 treatment of IDDM in NOD mice was partially mediated by serum factors including endogenous TNF.
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PMID:Inhibition of autoimmune diabetes in NOD mice with serum from streptococcal preparation (OK-432)-injected mice. 174 49

Diabetes in NOD mice is an autoimmune disease which is characterized by the infiltration of islets of Langerhans by large numbers of T cells. Some of these infiltrating T cells are clearly islet-cells-specific; however, many or most of these T cells could be attracted nonspecificity into these lesions. To study NOD pancreas-infiltrating T cells, we fused these cells with BW5147 to make T cell hybridomas. Ninety-four pancreas-derived T hybrids were analyzed of which 12 responded specifically to islet cells by secreting IL-2. Only CD3+, CD4+ hybrids responded to islet cells in our assay, and a large proportion of these hybrids were islet-cell reactive. T cell receptor (TCR) V beta element usage was heterogeneous in islet-reactive hybridomas.
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PMID:Analysis of pancreas-infiltrating T cells in diabetic NOD mice: fusion with BW5147 yields a high frequency of islet-reactive hybridomas. 183 36

Cytokines are known to play an important role in autoimmunity and have been suggested to be involved in the pathogenesis of insulin-dependent diabetes (IDDM). In the present study we have measured IL-1, IL-2, IL-4, IL-6, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) (using both immunoassays and bioassays) in sera from 50 patients affected by IDDM at the time of clinical diagnosis and 51 age and sex matched controls. Detectable levels of IL-1, IL-2, IL-6 and IFN-gamma were found in the serum of a small percentage of subjects and were not significantly different between patients and controls. IL-4 was detectable in a higher number of both patients and controls and circulating TNF-alpha (greater than 1 U/ml) was found in a percentage of patients (24%) significantly higher than controls (P less than 0.01). Raised levels of TNF-alpha were detectable using an immunoenzymatic assay whereas TNF bioactivity in these samples was negligible. We conclude that the presence of immunoreactive TNF-alpha in the patient's sera may reflect an increased localized production of this cytokine at pancreatic level. However, the measurement in serum of other cytokines does not add information on the role that they may play in the pathogenesis of IDDM.
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PMID:Cytokines in sera from insulin-dependent diabetic patients at diagnosis. 193 94

Chemically induced autoimmunity is a recently recognized environmental hazard that may affect individuals genetically predisposed to autoimmune disease and chronically exposed to certain chemicals. For example, moderate concentrations of mercury may lead to renal autoimmune disease in a small but significant percentage of the exposed population. Mercury also induces autoimmune glomerulonephritis in susceptible Brown Norway (BN) and MAXX inbred strain rats. Autoimmune responses, directed to epitopes of the renal glomerular basement membrane (GBM), are rapid in onset and have a self-limiting course in mercury-treated rats. Both regulatory T cells and idiotype-anti-idiotype network have been implicated in the resolution of this autoimmune process. In our investigations of immune regulation of mercury-induced autoimmune glomerulonephritis, we have used flow cytometry to quantitate lymphocyte subpopulations in the spleen and lymph nodes of mercury-treated and control BN rats. Of particular interest was the RT6+ T cell subset, that appears to have important immunoregulatory properties in a rat model of autoimmune insulin-dependent diabetes mellitus. Spleen and lymph nodes from control BN rats contained 22 and 52%, respectively, RT6+ cells. Spleens from mercury-treated animals contained 21% RT6+ cells on Day 10 of treatment, 13% on Day 17, 16% on Day 24 and 20% on Day 30. Lymph nodes from the same rats had 36% RT6+ cells on Day 10, 23% on Day 17, 29% on Day 24, and 28% on Day 30. The decrease in RT6+ cells correlated inversely with autoimmune responses to GBM, which peaked on Days 17-24 and declined by Day 30. Moreover, autoimmune responses were also associated with elevated RT6-:RT6+ T cell ratios. Similar results were obtained in two additional groups of BN rats, comprising both younger and older animals, sacrificed at Day 18 of mercury treatment. Analysis of other lymphocyte subpopulations demonstrated a decrease of CD4+ and CD5+ cells, whereas B cells as well as CD8+, IL-2 receptor+, and MHC class II+ subsets showed no consistent correlation with the onset or resolution of the autoimmune process. These findings suggest that mercury-induced changes in RT6+ T lymphocytes may be related to the development of renal autoimmune disease in genetically predisposed BN rats.
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PMID:Reduction of the RT6.2+ subset of T lymphocytes in brown Norway rats with mercury-induced renal autoimmunity. 201 77

Self-tolerance is generally induced by intrathymic clonal deletion of T cells with reactivity directed to antigens synthesized within the thymus (Kappler et al. 1987, Kisielow et al. 1988). It may also be induced in peripheral T cells when these encounter antigens unique to extra-thymic tissues. Two transgenic models have been particularly useful in the study of peripheral self tolerance: in one model, a known antigen is expressed in a particular extra-thymic site; in the other, the T-cell repertoire is predominantly reactive to this antigen. We, and others, have shown that expression of class I or II MHC molecules in defined extra-thymic sites leads to a state of T-cell tolerance. To account for this, we have proposed two hypotheses which have different implications for autoimmune disease. According to one, tolerance is imposed by deletion or functional silencing of specific high-affinity cytolytic T cells; alternatively, the target cell for tolerance induction may be a regulatory IL-2-producing T-cell, rather than the effector cell itself. To distinguish between these hypotheses it is essential to examine the fate of T cells which have the potential to react to the transgene product. Since the frequency of such T cells is low and there is no dominant clonotype for H-2Kb, which is the class I molecule we used, it was necessary to create double transgenic mice by mating class I transgenic mice with transgenic mice whose T-cell pool was compared of cells reactive to H-2Kb and could be detected by an antibody directed to the TCR. Initial studies showed that such T cells did persist despite the presence of antigen to which they may be reactive. If these double transgenic mice can be shown to be tolerant, they will offer a rich source of tolerant T cells for detailed investigation of their phenotype and fate, and they will be most useful in enabling us to probe the mechanisms responsible for the induction of peripheral self tolerance. Transgenic mouse technology has also been used successfully to unravel the genetic influences which may lead to or prevent autoimmunity. In particular, we have prevented autoimmune diabetes in the nonobese diabetic mouse by introducing a non-NOD MHC class II gene and further work is implicating the failure of intrathymic positive selection of a protective cell as one step in the pathogenesis of diabetes in NOD mice.
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PMID:Transgenic models of T-cell self tolerance and autoimmunity. 207 27

Intraperitoneal administration of human recombinant IL-2 led to a significant, dose-dependent increase and acceleration of diabetes development in BB rats, while we observed a suppression of diabetes development in animals with a high spontaneous disease incidence.
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PMID:[Interleukin-2 modifies the development of insulin-dependent diabetes of BB rats]. 235 12


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