Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have produced transgenic mouse strains harboring class II major histocompatibility complex or interferon-gamma genes linked to the human insulin promoter. These experiments were designed to investigate the consequences of the expression of immunological effector molecules by nonimmunological cells. In both of these studies we observed the disappearance from the pancreas of the insulin-producing beta cells coinciding with the development of insulin-dependent diabetes mellitus. Transgenic mice expressing both chains of the I-A gene showed progressive atrophy of the islets of Langerhans, whereas mice expressing interferon-gamma suffered an inflammatory destruction of the islets.
 ...
PMID:Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. 244 74

The BB rat spontaneously develops insulin-dependent diabetes mellitus (IDDM) as an autoimmune abnormality involving the class II molecules of the major histocompatibility complex (MHC). The rat MHC (RT1 complex) encodes two class II loci, RT1.B and RT1.D. The possibility that variant or unique class II MHC molecules may be associated with IDDM susceptibility was directly examined by determining the nucleotide sequences of class II mRNAs and/or cDNAs from the diabetes-prone (DP) BB rat, the diabetes-resistant (DR) BB rat, the normal histocompatible Wistar-Furth (WF) rat, and the Lewis rat. Sequence analysis indicates that the beta-chains of the RT1.B and RT1.D molecules of the u haplotype from DP-BB, DR-BB, and WF rats are identical but that they are different from other rat alleles and published mouse class II sequences. At the nucleotide level, the NH2-terminal domain of RT1.D beta of the BB and WF rats differs by a single silent nucleotide substitution. Comparisons with the sequences of the Lewis rat indicate hypervariable allelic differences and that the u and I haplotypes are remarkably similar. These findings establish that the class II molecules of the DP-BB rat are not variant or unique and that unaltered class II molecules of the u haplotype support the autoimmune response in the BB rat.
Diabetes 1989 Feb
PMID:Unaltered class II histocompatibility antigens and pathogenesis of IDDM in BB rats. 246 10

An immunogold-silver enhancement technique, which combines effective labeling of viable isolated islets with the ultrastructural resolution of cytological details, was applied in electron microscopy to identify major histocompatibility complex (MHC) structures on islet cells. Incubation of freshly isolated islets from CAP (RT1c) and LEW (RT1l) rats with OX18, an MHC class I antibody, showed strong positive reactivity in macrophages and/or dendritic-like cells (M0-DCs) and vascular endothelial cells (VEs) and a comparatively weaker reactivity in endocrine alpha-, beta-, and delta-cells. With MHC class II antibody OX6 (anti-I-A), M0-DCs were strongly labeled in both rat strains on the surface and on internal structures. Three of five particularly high titered batches of OX6 revealed MHC class II expression on VE and beta-cells. Four days of in vitro culture in combination with a high concentration of glucose and interferon-gamma induced strong enhancement of MHC class I structures and, to a lesser extent, class II structures on beta-cells.
Diabetes 1989 Jan
PMID:Immunoelectron microscopic localization of MHC structures in isolated pancreatic rat islets. 249 97

When highly purified neonatal rat islet tissue, derived after 10 days in vitro, was allografted, it was found to be nonimmunogenic or weakly immunogenic. In contrast, nonislet pancreatic components, derived from the same culture system, transplanted with highly purified islet tissue resulted in rejection in 88% of cases. Extension of the culture period did not result in reduced immunogenicity of the nonislet material. Immunostaining of islet or nonislet tissue from the culture system failed to demonstrate major histocompatibility complex (MHC) class II positive cells in the islet tissue, whereas the presence of MHC class II staining cells in the nonislet components was clearly demonstrable. These results demonstrate that the islet tissue obtained by culture isolation is free of cells capable of stimulating an allogeneic immune response and are consistent with the hypothesis that the absence of MHC class II positive antigen-presenting cells reduces the immunogenicity of the tissue and enhances the survival of allogeneic grafts.
Diabetes 1989 Feb
PMID:Allotransplantation of culture-isolated neonatal rat islet tissue. Absence of MHC class II positive antigen-presenting cells in nonimmunogenic islets. 249 74

INSULIN-dependent (type I) diabetes mellitus (IDDM) follows an autoimmune destruction of the insulin-producing beta-cells of the pancreas. Family and population studies indicate that predisposition is probably polygenic. At least one susceptibility gene lies within the major histocompatibility complex and is closely linked to the genes encoding the class II antigens, HLA-DR and HLA-DQ (refs 3, 4). Fine mapping of susceptibility genes by linkage analysis in families is not feasible because of infrequent recombination (linkage disequilibrium) between the DR and DQ genes. Recombination events in the past, however, have occurred and generated distinct DR-DQ haplotypes, whose frequencies vary between races. DNA sequencing and oligonucleotide dot-blot analysis of class II genes from two race-specific haplotypes indicate that susceptibility to IDDM is closely linked to the DQA1 locus and suggest that both the DQB1 (ref. 7) and DQA1 genes contribute to disease predisposition.
 ...
PMID:Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. 249 58

Insulin-dependent diabetes mellitus (IDDM) is caused by a specific loss of the insulin-producing beta cells from pancreatic Langerhans islets. It has been proposed that aberrant expression of major histocompatibility complex (MHC) class II molecules on these cells could be a triggering factor for their autoimmune destruction. This proposal was tested in transgenic mice that express allogeneic or syngeneic class II molecules on the surface of islet cells at a level comparable with that normally found on resting B lymphocytes. These animals do not develop diabetes, nor is lymphocyte infiltration of the islets observed. This immunological inactivity does not result from tolerance to the "foreign" class II molecules.
 ...
PMID:Transgenic mice with I-A on islet cells are normoglycemic but immunologically intolerant. 249 48

Cell line IgSV195, derived from a pancreatic tumor that arose in an SV40 T-antigen transgenic mouse, retains certain morphological and physiological characteristics of pancreatic beta-cells throughout in vitro and in vivo passage. Insulin secretion is stimulated by exposure of these cells to fetal bovine serum and a combination of 3-isobutyl-1-methylxanthine and glutamine but not by concentrations of glucose in the physiological range. Insulin processing appears to be intact. Neither class I nor class II major histocompatibility complex (MHC) antigens are routinely expressed at the cell surface; however, MHC class I--but not class II--encoded gene products are detected after treatment with recombinant interferon-gamma (IFN-gamma) alone or in combination with tumor necrosis factor. Cytolysis of IgSV195 cells by SV40 T-antigen-specific H-2b-restricted lymphocytes is similarly dependent on IFN-gamma pretreatment. These results emphasize that SV40 T-antigen transgenic mice are likely sources of cell lines that retain their differentiated function in vitro. The IgSV195 cell line provides an accessible model in which to investigate the control of gene expression and function of pancreatic beta-cells.
Diabetes 1989 Aug
PMID:Functional pancreatic beta-cell line from SV40 T-antigen transgenic mouse. 250 59

The NOD mouse has been recently developed as a model for autoimmune insulin-dependent diabetes mellitus. The NOD mouse is further characterized by a genetic linkage with genes mapping within the major histocompatibility complex at the I-A locus. The present work demonstrates the presence in NOD mice of circulating autoantibodies specific for a 58 kDa antigen which is present in membrane extracts prepared from the murine insulin-secreting tumoral cell line Rin5F. This 58 kDa antigen shows a cross reactivity with NOD mouse class II antigens as indicated by its recognition by anti-I-A(NOD) monoclonal antibodies.
 ...
PMID:[Cross-reactivity between major histocompatibility complex class II antigens in mice NOD and an islet antigen with 58 kDA molecular weight]. 250 91

Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice.
 ...
PMID:An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes. 250 22

Diabetes in the NOD mouse strain is a genetically programmed T cell-mediated autoimmune process that is directed against an as yet unknown antigen target(s) on pancreatic beta cells. To investigate whether the course of the autoimmune disease could be altered by immune manipulations of the T cell repertoire, we have induced allogeneic tolerance by injecting F1 semiallogeneic spleen cells into NOD neonates. This procedure resulted in a significant protection against both insulitis and diabetes. However, although it requires the induction of tolerance, as shown by the failure of non-tolerizing irradiated cells to prevent autoimmunity, protection appeared to be independent of the major histocompatibility complex haplotypes of the F1 spleen cells injected at birth, e.g. (C57BL/6 x NOD)F1, (CBA/Ca x NOD)F1 or (BALB/c x NOD)F1 cells. In addition, a similar degree of protection was induced, whether the tolerant state, as assessed by mixed lymphocyte reaction studies in vitro, was of short duration, approximately 6 weeks, or lasted for more than 12 weeks. Putative veto or suppressor functions of chimeric T cells were ruled out, since mice tolerized with T cell-depleted F1 spleen cells were equally protected. We conclude that the expression of spontaneous T cell-mediated autoimmunity can be modulated by immune manipulations at birth. Whether the protection observed in the present experiments resulted from the production of one or several specific holes in the autoimmune T cell repertoire, i.e. cross-tolerance, or whether it resulted from nonspecific disturbances of the emerging T cell repertoire remains to be elucidated.
 ...
PMID:Neonatal induction of allogeneic tolerance prevents T cell-mediated autoimmunity in NOD mice. 252 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>