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)

IFN-gamma is a cytokine with pleiotropic functions that participates in immune and autoimmune responses. The lack of IFN-gamma is known to delay the development of autoimmune diabetes in nonobese diabetic (NOD) mice. Splenocytes from diabetic NOD and IFN-gamma knockout (KO) NOD mice transfer diabetes into NOD recipients equally well. However, adoptive transfer of diabetogenic T cells from NOD mice into NOD.IFN-gamma-KO or NOD mice lacking beta-chain of IFN-gamma receptor (NOD.IFN-gammaRbeta-KO) appeared to be much less efficient. We found that IFN-gamma influences the ability of diabetogenic cells to penetrate pancreatic islets. Tracing in vivo of insulin-specific CD8+ T cells has shown that homing of these cells to the islets of Langerhans was affected by the lack of IFN-gamma. While adhesion of insulin-specific CD8+ cells to microvasculature was normal, the diapedesis was significantly impaired. This effect was reversible by treatment of the animals with rIFN-gamma. Thus, IFN-gamma may, among other effects, influence immune and autoimmune responses by supporting the homing of activated T cells.
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PMID:IFN-gamma affects homing of diabetogenic T cells. 1171 35

To analyze the function of the Th1-promoting cytokine IL-12 in vivo, we generated transgenic (tg) mice (RIP-IL12 mice) whose pancreatic beta cells constitutively express bioactive IL-12 or one of its components, p35 or p40. In contrast to non-tg littermates or single-tg RIP-p35 and RIP-p40 mice, RIP-IL12 mice developed a marked pancreatic infiltration of lymphocytes and macrophages, mainly around islets. Expression of bioactive IL-12 primarily upregulated transcript levels of IFN-inducible protein-10 (IP-10), RANTES, IFN-gamma, and TNF-alpha in the pancreas. Despite the substantial recruitment of mononuclear cells, no biochemical or clinical disease was evident in the exocrine or endocrine pancreas. Coexpression of lymphocytic choriomeningitis virus (LCMV) proteins with IL-12 in the beta cells failed to spontaneously activate or expand antigen-specific anti-self/viral T cells in uninfected tg animals. However, when RIP-IL12 x RIP-LCMV tg mice were infected with LCMV, antigen-specific anti-self/viral T cells were induced, which led to an acceleration in the kinetics and severity of insulin-dependent diabetes mellitus (IDDM). Thus, the ectopic expression of IL-12 does not spontaneously break tolerance and activate antigen-specific T cells in the periphery, but it does worsen ongoing autoimmune disease.
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PMID:Constitutive beta cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes. 1174 58

Linomide prevents the development of autoimmune insulitis and insulin-deficient diabetes mellitus in female NOD mice. Linomide prevents development of autoimmune manifestations in other experimentally induced and spontaneous autoimmune diseases as well, but the mechanism of action is unknown. The present report summarizes our investigations on the effect of Linomide on different functional T cell subsets in NOD mice analyzed according to their cytokine profile. Supernatants from cultured splenocytes and peritoneal cells taken from Linomide-treated mice contained lower levels of TNFalpha, IL-1 beta, IFN gamma and IL-12 versus higher levels of IL-4, IL-6 and IL-10 in comparison with supernatants from cultures of untreated mice. Our results suggest that regulation of autoimmunity following oral Linomide administration in NOD mice induces a shift from Th(1) to Th(2) phenotype response, thereby preventing the development of diabetes by active cytokine-induced immunoregulation of T cell subsets, including downregulation of Th(1) and upregulation of Th(2).
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PMID:Cytokine production in Linomide-treated nod mice and the potential role of a Th (1)/Th(2) shift on autoimmune and anti-inflammatory processes. 1218 43

This study was designed to examine the effects of administration of a plasmid encoding interferon(IFN)-gamma on reovirus type-2(Reo-2)-induced autoimmune insulitis in suckling DBA/1 mice. Cumulative incidences of diabetes and insulitis at 17 days post-infection in the mice treated with IFN-gamma-encoding plasmid were higher than those in control mice treated with "empty" plasmid. These results suggested that the IFN-gamma-encoding plasmid promoted autoimmune insulitis in Reo-2-induced diabetes.
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PMID:Plasmid encoding interferon-gamma exacerbates reovirus type-2-induced diabetes in DBA/1 suckling mice. 1235 32

Cytokines are the co-ordinators of the immune system and, as such, are important targets for immunomodulation. Progress has been made towards the use of IL-10 for immunosuppressive therapy to prevent autoimmunity. Interest has also recently focused on the role of cytokines in controlling the activation of dendritic cells and NK cells, and the consequences of this for the development of autoaggressive responses. Genes involved in IFN-activated pathways that control the survival of lymphocytes have been strongly linked to lupus susceptibility, and IFN-mediated defenses against viral infection have been shown to determine susceptibility to a model of viral-induced diabetes.
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PMID:Cytokines: promoters and dampeners of autoimmunity. 1241 31

IFN-kappa belongs to a recently identified subclass of type I IFNs. In this study, we report the cloning and preliminary characterization of the murine homologue of IFN-kappa. The gene encodes a 200-aa protein which is 38.5% homologous to human IFN-kappa. Murine IFN-kappa contains four cysteines in analogous positions to those observed in the IFN-alpha and an additional fifth unique cysteine, C174. The murine gene is located on chromosome 4, where other type I murine IFN genes, IFN-alpha and IFN-beta, are clustered. This region is syntenic with human chromosome 9 where the gene encoding IFN-kappa and the type I IFN gene cluster are found. Mouse IFN-kappa is expressed at low levels in peritoneal macrophages and its expression is up-regulated by dsRNA and IFN-gamma. Similar to previously reported transgenic mice carrying type I and type II IFNs, transgenic mice overexpressing murine IFN-kappa in the beta cells of the pancreas develop overt diabetes with hyperglycemia. Histological characterization of pancreatic islets from these transgenic mice showed inflammatory infiltrates with corresponding destruction of beta cells.
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PMID:Expression of a novel murine type I IFN in the pancreatic islets induces diabetes in mice. 1275 58

To date, there is no available treatment of hepatitis C virus (HCV) infection after renal transplantation (RT). Among 55 anti-HCV-positive/HCV RNA-positive hemodialysis patients who were treated with IFN-alpha (9 MU/wk during 6 or 12 mo), 21 of them (38%) had a sustained virologic response. Of these, 16 (76%) underwent RT 38 mo (range, 2 to 57 mo) after alpha-IFN therapy. There were 13 men and 3 women aged 46 yr (range, 27 to 68 yr). At RT, HCV serology was still positive in 15 patients, and HCV viremia was negative in all patients. Immunosuppression relied on anticalcineurin agents with or without steroids and/or antimetabolites; in addition, 12 of them received induction therapy with antithymocyte globulins. At the last follow-up after RT, at 22.5 mo (range, 2 to 88 mo), HCV viremia remained negative in all patients. Moreover, HCV RNA was not present in peripheral blood mononuclear cells when assessed in eight patients. HCV serology was found to be still positive in 13 patients. Three patients presented with acute rejection, one presented with a suppurative lymphocele, one died from a sepsis, and four presented with a cytomegalovirus infection. None of them developed posttransplant diabetes mellitus. In conclusion, hemodialysis patients waiting for a RT need to be treated with alpha-IFN because when HCV RNA clearance occurred, they experienced no relapse after transplantation despite chronic immunosuppressive treatment.
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PMID:Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. 1287 63

IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-gamma-producing CD4(+) cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.
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PMID:Systemic administration of IL-18 promotes diabetes development in young nonobese diabetic mice. 1463 96

Infection of the pancreas with lymphocytic choriomeningitis virus results in rapid and differential expression among CXCR3 chemokines. IFN-gamma-inducible protein of 10 kDa (IP-10), in contrast with monokine induced by IFN-gamma and IFN-inducible T cell-alpha chemoattractant, is strongly expressed within 24 h postinfection. Blocking of IP-10, but not monokine induced by IFN-gamma, aborts severity of Ag-specific injury of pancreatic beta cells and abrogates type 1 diabetes. Mechanistically, IP-10 blockade impedes the expansion of peripheral Ag-specific T cells and hinders their migration into the pancreas. IP-10 expression was restricted to viruses infecting the pancreas and that are capable of causing diabetes. Hence, virus-induced organ-specific autoimmune diseases may be dependent on virus tropism and its ability to alter the local milieu by selectively inducing chemokines that prepare the infected tissue for the subsequent destruction by the adaptive immune response.
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PMID:Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-gamma (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. 1466 90

Type 1 diabetes (T1D) is a T cell-mediated disease. Various DC populations play important roles in initiating and directing T cell responses and thus may be critical for T1D pathogenesis. We thus examined peripheral blood DC1 and DC2 populations by flow cytometry in healthy controls, subjects at risk for T1D, new-onset patients, and established T1D patients. We found a significant increase in the number of DCs (including DC1 and DC2) in at-risk subjects and those with new-onset T1D versus healthy controls and established T1D patients (ANOVA; p < 0.0001). Analysis of DC1 and DC2 subsets in these same groups demonstrated a significant decrease in the ratio of DC1 and DC2 in subjects at risk and new-onset and established T1D patients in contrast with healthy controls (p < 0.0001). Both subsets of peripheral blood DCs from T1D patients expressed significantly higher levels of HLA-DR than healthy controls. Peripheral blood mononuclear cells from T1D patients secreted significantly higher amounts of IFN-alpha than controls, and IFN-alpha production correlated inversely with the DC1/DC2 ratio. This study demonstrates a marked increase in peripheral blood DC numbers that occurs during a time of active autoimmunity in at-risk subjects and patients with new-onset T1D, but is lost in established diabetes. However, the abnormal distribution of peripheral blood DC populations appears to be a persistent phenotype in all stages of T1D.
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PMID:Abnormal peripheral blood dendritic cell populations in type 1 diabetes. 1467 64


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