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)

We have been successful in our efforts to develop a long lived noncytolytic murine IL-10/Fc fusion protein. In the nonobese diabetic mouse (NOD) model, administration of IL-10/Fc from 5 to 25 wk of age completely prevented the occurrence of diabetes. Moreover, these mice remained disease-free long after cessation of IL-10/Fc therapy. Immunohistochemistry studies show that IL-10/Fc treatment inhibits expression of TNF-alpha, proinflammatory cytokine, as well as Th1-type cytokines, IL-2 and IFN-gamma, but promotes expression of IL-4 and IL-10, Th2-type cytokines, by islet-infiltrating leukocytes. In an adoptive transfer model of diabetes in NOD mice, we found that: 1) IL-10/Fc treated hosts bear leukocytes that block expression of diabetes and 2) these leukocytes persisted even 8 wk after cessation of IL-10/Fc treatment. The potent antidiabetogenic effects provided by IL-10/Fc in the NOD model, together with its apparent lack of systemic toxicity, are notable.
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PMID:A noncytolytic IL-10/Fc fusion protein prevents diabetes, blocks autoimmunity, and promotes suppressor phenomena in NOD mice. 912 18

One of several possible mechanisms for the HLA-disease association is HLA-related polymorphism of cytokine expression. However, with the exception of the tumor necrosis factors, no evidence has been found for a relationship between HLA alleles and cytokine expression. This may be because cytokine responses to commonly employed mitogens are neither antigen nor HLA dependent, and responses to recall antigens are dominated by the effect of prior antigen exposure. We reasoned that responses to alloantigens would be independent of prior antigen exposure and may therefore reveal subtle HLA-related variations in cytokine production. Here we demonstrate HLA Class II-related polymorphism of IFN-gamma production in the MLR performed between 32 subjects by a novel whole-blood method. HLA DR1, 2, and 6 were associated with high, whereas DR 3, 4, 5, and 7 were associated with low IFN-gamma production. Interestingly, DQ alleles with which these DR alleles are in linkage dysequilibrium, DQ1 and DQ2 and 3, were also associated with high and low IFN-gamma production, respectively. Ranking of HLA alleles according to whole-blood IFN-gamma production in response to mitogen or recall antigens was similar to that in the MLR, although individual allele-related differences did not reach statistical significance. TNF-alpha production was significantly higher in DR3-positive than in DR3-negative subjects, in accord with previous studies. These findings suggest that HLA Class II alleles, particularly at the DQ locus, or alternatively, genes in linkage with them, regulate IFN-gamma expression by T cells. The finding of HLA allele-related polymorphism of IFN-gamma production corroborates other lines of evidence that regulation of IFN-gamma expression contributes to HLA-associated susceptibility to immunoinflammatory diseases, in particular insulin-dependent diabetes and multiple sclerosis.
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PMID:HLA class II-associated polymorphism of interferon-gamma production. Implications for HLA-disease association. 912 42

The mouse pancreatic beta TC3 and beta TC6-F7 cell lines were used to characterize the effects of interferon-gamma (IFN-y) on beta-cell phenotype and function. Initially, intracellular and secreted insulin were compared in glucose-stimulated cells over time. A significant reduction in insulin content and secretion was observed on a per-cell basis in glucose-stimulated beta TC3 and beta TC6-F7 cells after 12 h of exposure to IFN-gamma. The steadystate level of pre-proinsulin mRNA expression was not affected by IFN-gamma. Thus, we postulate that IFN-gamma's inhibitory actions occur after transcription of pre-proinsulin genes. Time-course analysis of IFN-gamma-regulated mRNA expression of the two intra-MHC-encoded subunits of the proteasome (low-molecular-mass polypeptide [Lmp]-2 and Lmp-7) revealed a correlation between their induction and the inhibitory effects of IFN-gamma on glucose-stimulated insulin production. Increased expression of Lmp-2 and Lmp-7 mRNA was accompanied by a corresponding induction of LMP2 and LMP7 protein expression. Subsequently, major histocompatibility complex (MHC) class I cell-surface expression was significantly increased in IFN-gamma-treated beta TC3 and beta TC6-F7 cells. Exposure of IFN-gamma-treated beta-cells to a peptide aldehyde inhibitor of the proteasome (MG132) significantly attenuated MHC class I cell-surface expression but did not prevent the negative effects of IFN-gamma on glucose responsiveness. Enhanced expression of the MHC class I antigen processing and presentation pathway and diminished insulin production appear to be distinct pathological alterations in beta-cells exposed to the insulitic cytokine IFN-gamma.
Diabetes 1997 May
PMID:Interferon-gamma independently activates the MHC class I antigen processing pathway and diminishes glucose responsiveness in pancreatic beta-cell lines. 913 43

Protective immunity to the parasitic nematode Onchocerca volvulus (Ov) appears to be directed against molecules of invading L3 larvae. In this study, the cellular immune reaction to such an Ov L3 protein (S1) which is protective in an animal model was analyzed using peripheral blood mononuclear cells (PBMC) of individuals from a hyperendemic area in West Africa who were exposed to Ov but remained free from disease ('putatively immune individuals'). Despite seronegativity of these individuals against S1, proliferation of PBMC was inducible, allowing generation of an S1-specific T cell line which produced IFN-gamma upon stimulation with both Ov lysate and S1. However, S1 induced significantly more IL-5 than Ov lysate. S1-specific, DQ6 (DQA1*0103/DQB1*0603)-restricted T cell clones were generated which reacted against synthetic peptides comprising amino acids 99-111 of S1. These clones, which are the first generated against a recombinant fllarial antigen, produced both IFN-gamma and IL-5 as well as little IL-4, suggestive of a Th0-like phenotype. In conclusion, in putative immunity, reactivity against a particular parasite protein can be detectable on the level of T but not B cells. Induction of both IFN-gamma and IL-5 by S1 suggests that it may trigger macrophage plus eosinophil dependent killing of L3 in vivo. The identification of a likely DQ6 (DQA1*0103/DQB1*0603)-restricted T cell epitope may be of more general relevance, given that allele combinations of DQ6, including DQA1*0103/DQB1*0603, are negatively associated with diabetes mellitus.
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PMID:Production of both IFN-gamma and IL-5 by Onchocerca volvulus S1 antigen-specific CD4+ T cells from putatively immune individuals. 918 17

The diabetes-resistant BioBreeding (DR-BB) rat, derived from diabetes-prone forebears, does not normally develop spontaneous insulitis or diabetes, but when infected with Kilham rat virus (KRV) this animal develops autoimmune diabetes similar to the diabetes-prone BioBreeding (DP-BB) rat. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play a role in the development of KRV-induced diabetes in DR-BB rats. Seventy-eight percent of DR-BB rats treated with KRV and poly(I:C) develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP) in KRV and poly(I:C)-treated DR-BB rats results in the near-complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-alpha, and IL-1beta revealed a selective increase of their expression, after KRV infection, in the splenic lymphocytes and the pancreatic islets. Measurement of CD4+ T cell-derived cytokines revealed that IL-2 and IFN-gamma cytokine gene expression closely correlates with an elevation of IL-12, but IL-4 and IL-10 do not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BB rats treated with KRV and poly(I:C) resulted in the loss of ability to transfer diabetes to young DP-BB rats. On the basis of these observations, we conclude that macrophages and macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic beta cells, culminating in the development of insulin-dependent diabetes mellitus.
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PMID:Role of macrophages and macrophage-derived cytokines in the pathogenesis of Kilham rat virus-induced autoimmune diabetes in diabetes-resistant BioBreeding rats. 920 Apr 87

We have previously shown that immunotherapy with complete Freund's adjuvant (CFA) or BCG is highly effective in the prevention of spontaneous insulin-dependent diabetes mellitus (IDDM) and in circumventing the rejection of syngeneic islet grafts in diabetic NOD mice. This protection is reversed by treatment with cyclophosphamide (Cy). The present study was undertaken to determine the effect of BCG vaccination on the progression of Cy-accelerated diabetes in NOD mice and to understand the mechanism of BCG immunotherapy. The time course of Cy and BCG administration showed that the progression of Cy-induced diabetes can only be blocked when BCG vaccination is given within 3 days of Cy administration. Mice given BCG 3 days before (-3 days) or 7 days after Cy treatment were not protected. BCG immunization 1 day after Cy treatment almost completely prevented insulitis in the islets of Cy-treated mice. Cy treatment reduced the endogenous production of anti-GAD67 antibody, whereas BCG vaccination 1 day after Cy treatment restored the production of anti-GAD67 antibody of IgG1 isotype. The comprehensive effect of BCG vaccination on cytokine production in Cy-treated mice was to increase IL-4 production and change the IL-4/IFN-gamma ratio in both serum and supernatant of spleen cell cultures. We found that BCG-induced protection was associated with increased splenic CD4+CD45 RB(high) T cells. Taken together, our results indicate that BCG treatment counteracts the effect of Cy on autoimmune process in IDDM. However, BCG immunotherapy has a narrow window of up to 3 days after Cy treatment to block the progression of Cy-induced diabetes and to allow for the induction of regulatory cells which may effectively downregulate the diabetogenic cells. In summary, our results suggest that BCG vaccination prevents IDDM if given in the prediabetic state. After the induction of diabetes, disease progression can only be prevented within a narrow window of opportunity by this treatment.
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PMID:BCG vaccination prevents insulin-dependent diabetes mellitus (IDDM) in NOD mice after disease acceleration with cyclophosphamide. 921 54

Oral administration of antigen leads to systemic immune unresponsiveness. Low dose oral tolerance generates regulatory cells which, when triggered in an antigen-specific manner, suppress inflammatory responses. We have previously shown that oral administration of an organ-specific antigen, porcine insulin, protects against diabetes development in the NOD mouse. In the present study we extend these observations to the B-chain of insulin, a 30-amino-acid peptide which has now been shown by others to contain the immunogenic epitope. Oral administration of the B-chain slowed diabetes development in a co-transfer model in which cells from B-chain-fed animals were co-transferred with diabetogenic cells (P=0.02). Further exposure to antigen via feeding of the co-transfer recipient animals not only slowed diabetes development but prevented diabetes in some animals (P=0.01). In vitro proliferation of popliteal lymph node cells from fed and immunized animals was suppressed in an antigen-specific manner when cells were restimulated with the fed antigen. When those cells were cultured and restimulated in vitro with the B-chain of insulin, we also observed a decrease in IFN-gamma expression and an increase in IL-4, TGF-beta and IL-10 expression. These results demonstrate that an orally protective epitope resides in the B-chain of insulin and that refeeding following adoptive transfer enhances protection. Finally, the orally administered antigen is associated with a decrease in Th1 responses and an increase in Th2 responses to the insulin B-chain.
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PMID:Oral administration of the immunodominant B-chain of insulin reduces diabetes in a co-transfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines. 923 97

The nonobese diabetic (NOD) mouse spontaneously develops T cell-dependent autoimmune diabetes. Here, we investigate the role of CD40 ligand (CD40L)-CD40 costimulation in the initiation and progression of this disease. Anti-CD40L mAb treatment of 3- to 4-wk-old NOD females (the age at which insulitis typically begins) completely prevented the insulitis and diabetes. In contrast, treatment of such mice with anti-CD40L at >9 wk of age did not inhibit the disease process. These results suggest that a costimulatory signal by CD40L is required early but not in the effector phase of disease development. Anti-CD40L treatment affected the priming of islet Ag-specific T cell responses in vivo. Cytokine analysis revealed a dramatic decrease in IFN-gamma and IL-2 release without a concomitant increase in IL-4 production by T cells from anti-CD40L-treated mice. Thus, anti-CD40L impaired the islet Ag-specific Th1 cell response in vivo, and the prevention of diabetes by anti-CD40L was not associated with switching of the response from a Th1 to a Th2 profile. Cotransfer of splenocytes from anti-CD40L-treated mice with splenocytes from diabetic NOD mice into NOD/scid mice did not inhibit the transfer of disease, indicating that anti-CD40L does not prevent the disease by inducing regulatory cells. Since anti-CD40L clearly prevented the insulitis by inhibiting the development and further accumulation of pathogenic Th1 cells to islets of Langerhans, we conclude that CD40L-CD40 costimulation is required for early events in the development of spontaneous autoimmune diabetes.
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PMID:CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice. 937 64

The BB rat model of human insulin-dependent diabetes mellitus (IDDM) spontaneously develops diabetes through an autoimmune process. Gamma interferon (IFN-gamma) is thought to play an important pathogenic role. This study examined if IFN-gamma administration can, paradoxically, prevent diabetes in BB rats. Diabetes-prone BB rats were initially injected intraperitoneally with murine recombinant IFN-gamma (rIFN-gamma) at doses of 0.5 x 10(4) to 40 x 10(4) U three times a week for 6 weeks beginning at 35 days of age. The effects of altering the duration of treatment (2 to 6 weeks) and the age at which injections were initiated (45 through 65 days) were also assessed. rIFN-gamma administration prevented the development of diabetes in a dose-dependent manner. The optimal treatment condition resulted in a 9.1% incidence of diabetes versus a 90% incidence in control rats. This diabetes-sparing effect was long lasting and continued to 7 months of age. A 4- to 6-week course resulted in maximal inhibition. Treatment initiated as late as 55 days of age, when insulitis is already present, was effective in preventing diabetes. Islet inflammation was dramatically lower in rIFN-gamma- versus saline-injected rats (P < 0.01). Total leukocyte count and subpopulations of peripheral mononuclear cells were unaltered by rIFN-gamma. In summary, rIFN-gamma paradoxically and potently prevents diabetes in BB rats in a dose-dependent fashion by inhibiting islet inflammation. This diabetes-sparing effect occurs even when injections are initiated after evidence of the diabetic process is already present.
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PMID:Gamma interferon prevents diabetes in the BB rat. 938 4

A single injection of syngeneic islet cells into the thymus of 4-week-old NOD/Lt female mice strongly retards diabetogenesis. The present study used the intrathymic route of antigen administration to compare the relative efficacy of peptides/proteins derived from two major candidate pancreatic beta-cell autoantigens, insulin and GAD65, to modulate diabetogenesis. Intrathymic administration of insulin B chain or recombinant human GAD65 significantly suppressed diabetogenesis during a 20-week follow-up period, whereas no protection was mediated by either insulin A chain or a synthetic peptide (A2) derived from it. Quite unexpectedly, two GAD65-derived peptides near the COOH-terminus (p34 and p35) accelerated diabetes onset. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed on cDNAs from isolated islets or whole pancreases of NOD/Lt females 4 weeks after intrathymic injections. Protection mediated by intrathymic administration with either intact islet cells or GAD65 were correlated with an upregulation of mRNA for T-helper 2 (Th2)-associated cytokines (interleukin [IL]-4, IL-10), concomitant with downregulation of Th1-associated interferon (IFN) transcripts (all normalized to T-cell receptor Cbeta transcripts) in islet-infiltrating lymphocytes. Protection mediated by the intrathymic administration of insulin B chain, however, correlated only with a modest upregulation of IL-4 and IL-10 transcript levels, and no diminution in IFN-gamma transcripts. In contrast, the diabetes-accelerating GAD65 p34 and p35 peptides were not associated with an immune deviation, expressing levels of IFN-gamma characteristic of islet-infiltrating lymphocytes in vehicle-injected NOD controls. Hence, Th1-to-Th2 immune deviation provides only a partial explanation for peptide immunotherapy of diabetes in NOD mice. The finding that certain peptides can accelerate rather than retard diabetogenesis as a function of route and age of administration adds a cautionary note to this type of therapy.
Diabetes 1997 Dec
PMID:Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate beta-cell antigens. 939 83


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