UMLS:C0011849 - FACTA Search

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

Cytokines have been shown to play an important role in regulating tolerance to islet Ags and provoking destructive islet lesions. However, data from a number of experimental systems have been conflicting, and the role of cytokines produced by T lymphocytes at various stages of diabetes has not been clearly defined. We have studied the production of cytokines in the pancreas during the development of autoimmune diabetes induced in mice by administration of (5) low doses of streptozotocin (STZ) (MDSDM). Diabetes in this model is T lymphocyte dependent. We used techniques of semiquantitative PCR to identify and quantitate cytokines that are produced. We have found that IL-2, IL-4, TNF-alpha, and IFN-gamma are expressed by the time the fourth dose of STZ is given. In the same pancreas, all of these cytokines (including IL-4) may be found. However, expression of IFN-gamma, but not IL-4, was limited to intrapancreatic lymphocytes and was not detectable at extrapancreatic lymphoid sites. Moreover, mAbs against IFN-gamma, but not against IL-4 or IL-2, prevent hyperglycemia and insulitis in MDSDM, suggesting that IFN-gamma regulates development of disease. Cells in the pancreases of nondiabetic mice treated with anti-IFN-gamma mAb and STZ show enhanced expression of IL-4, but the prevention of disease is due to blockade of the IFN-gamma itself, and not due to secretion of IL-4, because systemic administration of IL-4 does not prevent MDSDM. Thus, our findings indicate that cytokines produced by Th1 (or T cytolytic 1) and Th2 (or T cytolytic 2) cells are found in the pancreases of mice developing autoimmune diabetes. IFN-gamma is responsible for progression to diabetes, and its production is limited to lymphocytes only at that site.
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PMID:Regulation of cytokine production during development of autoimmune diabetes induced with multiple low doses of streptozotocin. 861 81

Cytokines produced by islet-infiltrating mononuclear leukocytes may be involved in islet beta-cell destruction and IDDM. To determine which cytokine(s) might be involved in islet beta-cell destruction, we used a reverse transcriptase-polymerase chain reaction assay to compare levels of cytokine mRNA expression in mononuclear leukocytes freshly isolated from islets of four groups of BB rats aged 60-75 days: diabetes-prone (DP) rats, DP rats protected from diabetes by injection of complete Freund's adjuvant (CFA) at age 25 days, acutely diabetic rats, and diabetes-resistant (DR) rats. We found that islet mononuclear leukocyte levels of gamma-interferon (IFN-gamma) mRNA were significantly higher in DP and diabetic rats than in DR rats, whereas CFA-treated DP rats had similar IFN-gamma mRNA levels to DR rats. Also, interleukin (IL)-2 mRNA levels tended to be higher in islet leukocytes from DP and diabetic rats than from DR rats. Tumor necrosis factor-alpha, IL-4, and IL-10 mRNA levels were not significantly different in islet leukocytes from the four groups of rats. These findings suggest that production of T-helper 1 (Th1)-type cytokines, IFN-gamma and IL-2, by islet-infiltrating cells in BB rats is associated with beta-cell destruction and IDDM development.
Diabetes 1996 Jun
PMID:Cytokine gene expression in pancreatic islet-infiltrating leukocytes of BB rats: expression of Th1 cytokines correlates with beta-cell destructive insulitis and IDDM. 863 48

We previously reported the generation and characterization of a panel of CD4(+) autoreactive T cell clones that suppress development of autoimmune diabetes in non-obese diabetic (NOD) mice. We showed that the protective capacity of the T cell clones correlated with secretion of an activity that potently inhibits allogeneic mixed lymphocyte reaction (allo-MLR). In this report, we describe the biological characteristics of the allo-MLR inhibitory activity (MLR-IA, short for mixed lymphocyte reaction inhibitory activity) secreted by the protective T cell clone, NOD-5. MLR-IA has little effect on initiation of proliferation in an allo-MLR, but it potently inhibits the maintenance and amplification of the proliferative response. MLR-IA is also capable of inhibiting concanavalin A (Con A) stimulated splenic responder T cell proliferation. MLR-IA is reversible in vitro and is not restricted by MHC class I or II proteins. MLR-IA does not affect IL-2 receptor expression of responding T cells and has no effect on IL-2-dependent proliferation of CTLL-20 T cells. Partially purified MLR-IA inhibits IL-2 production in a primary allo-MLR, and decreases IFN-gamma production during secondary allo-MLR and Con A activation, whereas it enhances IL-4 production in both primary and secondary Con A activation. MLR-IA is not neutralized by combination of antibodies specific for transforming growth factor-beta, IL-10, tumor necrosis factor-alpha/beta or IFN-gamma, suggestive of a novel activity. MLR-IA is ammonium sulfate precipitable, sensitive to protease digestion and is destroyed by boiling, indicating that a protein moiety is part of its active structure. Our work suggests that a potentially novel immunoregulatory activity, capable of inhibiting T lymphocyte proliferation and IFN-gamma production, and stimulating IL-4 production, may regulate development of autoimmune diabetes in NOD mice.
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PMID:Biological characteristics of an immunoregulatory activity secreted by an autoreactive CD4+ T cell clone that suppresses autoimmune diabetes in non-obese diabetic mice. 867 56

NOD mice constitute a model for studying the prevention of human autoimmune type 1 diabetes. Glutamic acid decarboxylase (GAD) could be a key antigen involved in this disease, and GAD65 peptide 524-543 has been implicated in early T cell response in young NOD mice. We performed two i.p. injections of GAD peptide 524-543 (100 micrograms at each injection), together with Freund's incomplete adjuvant (FIA), into female NOD mice at 30 and 45 days old. Diabetes was accelerated 2 weeks later by a single injection of cyclophosphamide (CY), which acts against suppressive mechanisms. Treatment with GAD 524-543 peptide delayed the onset of diabetes and reduced its incidence (28% versus 60%; P < 0.001) compared with control mice injected with FIA alone, or GAD peptide 534-553, or an irrelevant peptide. In the same group, the severity of lymphocytic inflammation of pancreatic islets was reduced (P < 0.03). Up to 3 months after peptide injections, a strong splenocytic proliferative response occurred in immunized NOD mice against the immunizing peptide alone (but not against a panel of seven other GAD65-derived peptides). After peptide challenge of splenocytes in vitro, protection against CY-accelerated diabetes was associated with higher peptide-specific production of T helper type 2 (Th2)-associated interleukins 4 and 10, whereas Th1-associated interferon-gamma and IL-2 were proportionally less represented. During contransfer, T splenocytes from GAD 524-543-immunized mice were able to reduce the capacity of T cells from diabetic donors to transfer the disease adoptively (P < 0.01), demonstrating the generation of cellular mechanisms that actively suppress the disease. It is concluded that immunization of NOD mice with GAD65 peptide 524-543 can counteract CY-accelerated diabetes, possibly through active cellular suppression linked to a shift of Th1/Th2 balance toward the production of Th2 cytokines such as IL-4 and IL-10. This study provides additional support for the notion that GAD, and more precisely its epitope 524-543, could be one of the key targets for the pathogenesis of type 1 diabetes in NOD mice, as well as for the efficacy of disease-specific peptide therapy in type 1 diabetes.
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PMID:Immunization of non-obese diabetic (NOD) mice with glutamic acid decarboxylase-derived peptide 524-543 reduces cyclophosphamide-accelerated diabetes. 870 42

Expression of the co-stimulatory molecule B7-1 (CD80) on pancreatic beta cells can overcome peripheral T cell tolerance in transgenic models of autoimmune disease. This study aimed to determine if aberrant B7-1 or B7-2 (CD86) expression on pancreatic beta cells is involved in the pathogenesis of autoimmune diabetes in non-obese diabetic (NOD) mice. Immunohistochemical analysis of NOD pancreas sections revealed no evidence of B7-1 or B7-2 expression on pancreatic beta cells at any stage prior to the onset of either spontaneously arising or cyclophosphamide-accelerated diabetes. Likewise, the NOD-derived NIT-1 beta cell line did not express surface B7 or B7-1 mRNA either constitutively or following exposure to IFN-gamma and TNF-alpha, two cytokines known to be present in the insulitis lesion of NOD mice, or cAMP which can induce B7-1 expression on B cells. Both B7-1 and B7-2 were, however, highly expressed on the majority of islet-infiltrating inflammatory cells in NOD mice between days 7 and 12 after the administration of cyclophosphamide which results in accelerated beta cell destruction. Likewise B7-1 and B7-2 were extensively expressed on islet-infiltrating cells present at the time of diabetes onset in NOD SCID mice with adoptively transferred diabetes. By immunohistochemistry and flow cytometry, it was determined that the phenotype of B7+ cells in the pancreas of NOD mice 9 days after cyclophosphamide included a mixture of macrophages and both CD4+ and CD8+ T cells. B7-2 was also expressed on islet-infiltrating cells in the spontaneously occurring diabetes of female NOD mice, but the levels of B7-1 expression were low in comparison with the accelerated models of diabetes. RIP-IL-2 transgenic mice, which have extensive islet infiltration but no autoimmune beta cell destruction, also had virtually no B7-1 expression and a minority of B7-2-expressing inflammatory cells. Thus, the activation of beta cell-specific T cells in NOD mice does not appear to be a result of aberrant expression of B7 on the beta cells. Expression of B7-1 and B7-2 on islet-infiltrating cells is, however, associated with autoimmune beta cell destruction, suggesting a role for the B7-CD28 interaction in this process.
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PMID:Pancreatic expression of B7 co-stimulatory molecules in the non-obese diabetic mouse. 874 58

This study was designed to determine the effect of Type II diabetes mellitus in older adults on two measures of the cell-mediated immune response to influenza vaccination. Twenty-two elderly persons with diabetes mellitus were compared to 20 healthy seniors, all of whom were living independently in the community. Peripheral blood mononuclear cells (PBMC) were challenged in vitro with live influenza virus, pre-vaccination and 4 and 12 weeks post-vaccination. PBMC culture supernatants were assayed for IL-2 activity as a measure of the helper T-cell response to vaccination. The cytotoxic T-lymphocyte response was determined using an assay of granzyme B activity in PBMC lysates. Initial analysis of the data showed increased IL-2 production in post-vaccination PBMC cultures from the diabetic group compared to the healthy group. However, when vaccination histories were used in an analysis of variance, it was found that the difference between the two groups was related to vaccination history. Study subjects vaccinated one year prior to participation in this study compared to those who had not been previously vaccinated, demonstrated a significantly suppressed IL-2 response to vaccination. Type II diabetes mellitus had no effect on the IL-2 response to vaccination. The granzyme B response to vaccination was not significantly affected by previous vaccination and results were similar for the healthy and diabetic elderly groups.
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PMID:Helper and cytotoxic T lymphocyte responses to influenza vaccination in healthy compared to diabetic elderly. 878 53

CD28 ligation delivers a costimulatory signal important in T cell activation. This study demonstrates that the disruption of the CD28/B7 pathway early in the nonobese diabetic mouse strain, using CD28-/- and CTLA41g transgenic mice, promoted the development and progression of spontaneous autoimmune diabetes. Functional analyses of T cells isolated from CD28-deficient mice demonstrated that the GAD-specific T cells produced enhanced Th1-type cytokines (IL-2 and IFN gamma) and diminished Th2-type cytokine, IL-4. Moreover, there was a significant decrease in serum levels of anti-GAD antibodies of the IgG1 isotype consistent with a profound suppression of Th2-type responses in these animals. Thus, the early differentiation of naive diabetogenic T cells into the Th2 subset is dependent upon CD28 signaling and extends our understanding of the importance of Th1/Th2 balance in the regulation of this spontaneous autoimmune disease.
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PMID:CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. 880 83

Th1 cytokines are thought to play a key role in islet inflammation and destruction in insulin-dependent diabetes mellitus (IDDM). We studied this hypothesis in the diabetes-prone (DP)-BB and the diabetes-resistant (DR)-BB rats that are used as a model of human IDDM. The DP-BB rat develops spontaneous autoimmune diabetes at the age of 11-14 weeks. In the DR-BB rat, diabetes is inducible by depletion of RT6+ lymphocytes and coadministration of polyinosinic:polycytidylic acid (Poly I:C). We used reverse transcriptase-polymerase chain reaction (RT-PCR) and semi-quantitative PCR techniques to examine mRNA expression of Th1 and Th2 cytokines in inflamed islets and thyroids from DP-BB and DR-BB rats. We observed that in DP-BB and in treated DR-BB rats, the levels of TCR beta, IFN-gamma and IL-12p40 mRNA increase with disease progression. In contrast, expression of message for IL-2 and IL-4 is minimal to undetectable in DP-BB and RT6-depleted DR-BB animals at any age. Message for IL-10 is detectable in DP and DR islets; however, its level of expression does not change with disease progression. A similar cytokine mRNA profile is observed in inflamed thyroids from acutely diabetic RT6-depleted DR-BB rats. Incubation of 10 wk old DP islets for 48 h in the presence of anti-CD3 antibody, followed by an incubation with rIL-2 for an additional 5-7 days, results in an expansion of T lymphocytes, and these cells express high levels of IFN-gamma and IL-10 mRNA. Our results suggest that autoimmunity in DP-BB and DR-BB rats is mediated by Th1 lymphocytes and that IFN-gamma and IL-12 are likely to play a key role in islet and thyroid inflammation and destruction in IDDM.
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PMID:Evidence that Th1 lymphocytes predominate in islet inflammation and thyroiditis in the BioBreeding (BB) rat. 881 66

The non-obese diabetic (NOD) mouse develops diabetes as a result of spontaneous T cell mediated destruction of the insulin-producing beta-cells. Tolerization to glutamic acid decarboxylase (GAD65) has been reported to inhibit spontaneous T cell proliferative responses to GAD65 and GAD65 peptides and prevent insulitis and diabetes in NOD mice. To evaluate the role of T cells responsive to GAD65 in induction of diabetes in NOD mice we generated T cell clones from spleen cells of three prediabetic NOD mice using the reported immunodominant human GAD65 peptides nos. 17, 34 and 35, which are spontaneously recognized by NOD spleen cells. The ten T cell clones established from two female and one male NOD mice recognized either the GAD65 peptide no. 35 which has an identical amino acid sequence in mice and humans or recognized the human GAD65 peptide no. 17 which is different in two amino acids from murine GAD65 peptide no. 17. None of the clones exhibited responses to islet cells, and GAD65 peptide no. 17 responsive clones did not cross react with the murine GAD65 peptide no. 17. All clones were CD4 positive and expressed the alpha/beta T cell receptor, but differed in their V beta usage. Analysis of in vitro production of IFN gamma, IL-2 and IL-4 demonstrated a TH1 and TH0 like functional subset of the individual clones. In vivo, neither the autoreactive T cell clones specific for GAD65 peptide no. 35 nor the xenoreactive clones specific for GAD65 peptide no. 17 were able to accelerate diabetes in young NOD mice or transfer diabetes into NODscid mice.
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PMID:Peripheral T cell clones from NOD mice specific for GAD65 peptides: lack of islet responsiveness or diabetogenicity. 881 71

Insulin-dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse results from a T lymphocyte mediated destruction of the insulin-producing beta cells of the pancreas and serves as a model for human type I diabetes. The NOD mouse develops insulitis at 4 weeks of age and diabetes later in life. It has previously been shown that a T helper 1 (Th1) response to the islet antigen, glutamic acid decarboxylase (GAD65, henceforth GAD) spontaneously develops in NOD mice concurrent with the onset of lymphocytic infiltration into the islets (insulitis). The proliferative T cell response in the spleen is initially confined to the carboxy-terminal region of GAD65 (peptides 509-528 and 524-543) followed by a progression to nearby determinants and a variety of upstream determinants. We have produced a set of overlapping synthetic peptides spanning the 509-543 region of GAD and surveyed the responses raised by immunization with peptide GAD(524-543), which is the more immunogenic of the two peptides. NOD mice immunized with GAD(524-543) demonstrate splenic proliferative responses to 524-538 and 527-541 but not to 521-535 or 530-543. Four T cell hybridomas were produced from spleen cells of GAD(524-543)-immunized NOD female mice. Each hybridoma displayed a unique cytokine profile when stimulated with peptides 524-538 and 527-541, assaying IL-2, IFN-gamma, and IL-5 production by peptide-stimulated hybridomas. To identify MHC and TCR contact residues critical for the stimulation of the hybridomas, a truncated peptide (GAD 526-538) and a panel of analogue peptides were synthesized containing single-amino acid substitutions. Hybridoma 35.13.2 was non-responsive to the truncated peptide and all of its variants. However, the four residues 530 (A), 531 (P), 536 (R), and 537 (M) were found to be critical for the activation of the three remaining hybridomas, suggesting that these positions in the GAD-524-543 determinant were MHC binding residues or conserved TCR contact sites.
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PMID:T cells with multiple fine specificities are used by non-obese diabetic (NOD) mice in the response to GAD(524-543). 881 72

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