Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751781 (NOD)
 6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We used NOD mice to investigate the effects of injecting transduced lymphocytes on insulitis, nonfasting blood glucose levels, and immune responses. Syngeneic splenocytes were transduced with retroviral particles carrying a cDNA construct encoding the beta cell antigen glutamic acid decarboxylase (GAD65), a secreted form of GAD65 (SGAD55), or secreted alkaline phosphatase (SEAP) as a control antigen. Different multiplicities of infection (m.o.i.) were used with different constructs. Four-week-old NOD mice received intravenous injection of CD4(+) cells isolated from transduced splenocytes, and insulitis and blood glucose levels were determined at 10 weeks of age. No significant effects were observed with lymphocytes transduced with gad65 and sgad55 constructs at low m.o.i. By contrast, at high m.o.i., lymphocytes transduced with the sgad55 and seap constructs caused a decrease in insulitis and blood glucose levels and in insulitis alone, respectively. ELISA of anti-GAD antibody isotypes indicated that GAD-transduced lymphocytes induced similar Th2-like responses at all m.o.i. These results suggest that retroviral particles carrying sgad55 can be used for engineering cell vaccines for type 1 diabetes and provide further evidence that Th2-like responses induced by immunization may not always be a primary cause of diabetes suppression in NOD mice.
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PMID:Decreased insulitis and blood glucose levels after injection of GAD-transduced lymphocytes into NOD mice. 1249 66

While both isoforms of glutamic acid decarboxylase (GAD) function as important autoantigens in autoimmune diabetes mellitus-GAD65 in humans and GAD67 in the NOD mouse-GAD67 is not synthesized in human pancreatic islets and is thought not to be an autoantigen in human diabetes. We have recently shown, however, that human islets contain a GAD67 splice variant: GAD25. Given the evidence that GAD67 could be a key diabetogenic autoantigen in the NOD mouse and the high prevalence of GAD65 autoantibodies in human type 1 diabetes, it became important to ask whether there is also immune reactivity to GAD25 in type 1 diabetes-possibly implicating it in the pathogenesis of the disease-and whether GAD25 reactivity could, like GAD65 reactivity, function as a clinically useful marker for the disease. We also hypothesized that the presence of autoantibodies to the smaller splice variant could be a cause of the up to 30% prevalence of GAD67 autoreactivity associated with type 1 diabetes. We therefore analyzed GAD25 reactivity in 105 newly-diagnosed children with type 1 diabetes and 74 control subjects. While 14 (13%) of the diabetic subjects were positive for GAD67 autoantibodies, only 3 (3%) were positive for GAD25 reactivity, none of which were GAD67 antibody-positive. Analysis of reactivity to a GAD67 chimera was consistent with GAD67 binding activity being due to cross-reactive GAD65 antibodies. Immunostaining confirmed the presence of GAD25 in human islets, revealing GAD25-positive cells to be sparse. Our results indicate that autoreactivity to GAD25 is rare in newly diagnosed type 1 diabetes and does not underlie GAD67 reactivity.
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PMID:Immune reactivity to GAD25 in type 1 diabetes mellitus. 1251 88

B lymphocytes partially contribute to autoimmune type 1 diabetes (T1D) as a subset of APC with a preferential ability to trigger pathogenic CD4 T cells. We hypothesized that this resulted from the unique ability of B lymphocytes to take up pancreatic beta cell proteins through Ig mediated capture. T1D was significantly delayed, but not prevented, in a NOD stock in which the B lymphocyte Ig repertoire was strongly restricted because of the allelic exclusion induced by transgenic Ig molecules specific for the disease irrelevant hen egg lysozyme (HEL) protein (NOD.IgHEL mice). However, introducing the Ig(mu)null mutation to eliminate the small residual numbers of non-transgenic B lymphocytes in the NOD.IgHEL stock strongly suppressed T1D to the same low levels that characterize B lymphocyte deficient NOD.Ig(mu)null mice. In contrast to standard NOD mice, both the NOD.IgHEL.Ig(mu)null and NOD.Ig(mu)null stocks were unable to generate T cell responses against the candidate diabetes autoantigen, glutamic acid decarboxylase. These results indicate that Ig-mediated capture of beta cell autoantigens accounts for why B lymphocytes have a greater capacity than other APC subtypes to trigger diabetogenic T cells. Hence, defects in B lymphocyte, as well as T lymphocyte, tolerance induction mechanisms may contribute to T1D in NOD mice.
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PMID:The preferential ability of B lymphocytes to act as diabetogenic APC in NOD mice depends on expression of self-antigen-specific immunoglobulin receptors. 1251 57

Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2-deficient 129 mice onto the NOD background along with 16 genetic markers (including I-A(g7) MHC molecule) associated with diabetes. Intercross mice from the fourth backcross generation showed that proinsulin 2(-/-) mice develop accelerated insulitis and diabetes. The high prevalence of anti-insulin autoantibodies in proinsulin 2(-/-) mice indicates that diabetes acceleration relates to altered recognition of proinsulin. The prevalence of anti-glutamic acid decarboxylase autoantibodies and of sialitis is not increased in proinsulin 2(-/-) mice. We give evidence that proinsulin 2 expression leads to silencing of T cells specific for an epitope shared by proinsulin 1 and proinsulin 2. In the human, alleles located in the VNTR region flanking the insulin gene control beta cell response to glucose and proinsulin expression in the thymus and are key determinants of diabetes susceptibility. Proinsulin 2(-/-) NOD mice provide a model to study the role of thymic expression of insulin in susceptibility to diabetes.
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PMID:Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. 1263 91

Genetic vaccines are promising candidates for prevention of type 1 diabetes, an autoimmune disease resulting from cell-mediated destruction of pancreatic beta cells. It is known that the prophylactic effect and immune responses induced by administration of a genetic vaccine can depend on site of delivery. In the work presented here, we used the NOD mouse model for type 1 diabetes to evaluate different routes of delivery for DNA vaccines coding for the beta-cell antigen glutamic acid decarboxylase (GAD). Plasmid DNA coding for intracellular or secreted GAD was given via either the intramuscular (i.m.), intradermal (i.d.), or oral route, using, respectively, 300, 100, or 300 micro g DNA per mouse. Results indicated that both i.d. and oral delivery of GAD-encoding DNA were more effective than i.m. delivery for disease suppression. In addition, cytokine-specific ELISpot analysis indicated that immune responses induced by the different immunization protocols were more dependent on the cellular localization of GAD antigen than on the delivery route, while ELISA of anti-GAD serum antibody isotypes indicated that i.d. delivery of DNA was most likely to induce a Th2-like response. Our results suggest that i.d. or oral delivery of a genetic vaccine for type 1 diabetes might be preferable over the i.m. route in a future clinical setting.
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PMID:Intradermal or oral delivery of GAD-encoding genetic vaccines suppresses type 1 diabetes. 1282 99

Peptide-mediated immunotherapy has been studied in a number of experimental models of autoimmune diseases and has also been tested in human patients to a certain extent. Copolymer 1 is a synthetic amino acid copolymer that has been demonstrated to suppress experimental autoimmune encephalomyelitis (a model for multiple sclerosis) when administered parenterally. Some study results indicate that mucosal tolerance induced by appropriate recombinant peptide fragments of human AChR is effective in suppressing experimental autoimmune myasthenia gravis and might be considered as a therapeutic modality for patients with MG. A peptide of the heat-shock protein 60 molecule, designated peptide p277, was shown to be a target of T cells in autoimmune diabetes in NOD mice, and intraperitoneal injections of glutamic acid decarboxylase (GAD) peptide 524-543 delayed the onset of diabetes and significantly reduced its incidence. Experimental evidence has revealed that CDR-based peptides may be potential candidates for the therapy of systemic lupus erythematosus. The use of synthetic peptides that focus on neutralization of pathogenic anti-beta 2GPI antibodies represents a possible new therapeutic approach to antiphospholipid syndrome. Studies in both acute and chronic-relapsing experimental autoimmune uveoretinitis have indicated that oral administration of S-Ag, S-Ag-derived peptides, inter-photoreceptor retinoid binding protein or HLA-derived peptides before immunization can protect animals from the disease.
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PMID:Peptide immunotherapy in autoimmune diseases. 1293 33

Type 1 diabetes (T1DM) results from a failure of central and peripheral tolerance to islet cell antigens. ICA69 belongs to a group of molecules expressed predominantly in neuroendocrine tissues (including pancreatic islets), which are targets of autoimmune responses in T1DM. These molecules are also expressed in the thymus and peripheral lymphoid organs by dendritic cells. The aim of the present study was to evaluate possible variation in thymic ICA69 expression, comparing diabetes-resistant controls to T1DM-prone NOD mice. Thymic tissue was retrieved from 3- to 6-week-old female B6, NOD-H2(b), and NOD mice. Paraffin-embedded sections were stained with an ICA69-specific antibody in an immunoperoxidase assay. ICA69 staining of thymic sections from B6 and NOD.H2(b) showed strong and continual staining, yet the sections from the NOD mice showed significantly reduced staining for ICA69. Corroboration of the reduced level of ICA69 in the thymus of NOD mice has been obtained via analysis for the expression of ICA69 versus other candidate autoantigens (glutamic acid decarboxylase 65, glutamic acid decarboxylase 67, and insulin 2) in the thymus. Real-time PCR analysis, using cDNA generated from the thymus, displayed that the expression of GAD65, GAD67, and INS2 were equivalent when comparing NOD at any age to B6, BALB/cJ, and ALR/LtJ. In marked contrast, the level of ICA69 in the thymus of the NOD mice examined was significantly reduced when compared to the controls. In fact, the real-time PCR analysis strongly suggested that ICA69 was not expressed in the thymus of NOD mice. These findings support the hypothesis that the level of thymic ICA69 expression may be of importance in regulating self-tolerance in T1DM.
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PMID:Reduced thymic expression of islet antigen contributes to loss of self-tolerance. 1467 3

Immunization of NOD mice with autoantigens such as glutamic acid decarboxylase (GAD) 221-235 peptide (p221) can induce Ag-specific CD4(+) T regulatory (Tr) cells. However, it is unclear whether these Tr cells acquire their regulatory capacity due to immunization or whether they are constitutively harbored in unimmunized naive mice. To address this question, we used an I-Ag7 tetramer to isolate p221-specific T cells from naive NOD mice (N221(+) cells) after peptide-specific in vitro expansion. The N221(+) T cells produced IFN-gamma and IL-10, but very little IL-4, in response to p221 stimulation. These T cells could function as regulatory cells and inhibit in vitro proliferation of diabetogenic BDC2.5 cells. This suppressive activity was cell contact-independent and was abrogated by Abs to IL-10 or IL-10R. Interestingly, IL-2 produced by other T cells present in the cell culture induced unactivated N221(+) T cells to exhibit regulatory activities involving production of IL-10. In vivo, N221(+) cells inhibited diabetes development when cotransferred with NOD splenocytes into NOD/scid recipients. Together, these results demonstrate that p221-specific IL-10-dependent Tr cells, including Tr type 1 cells, are present in naive NOD mice. The use of spontaneously arising populations of GAD peptide-specific Tr cells may represent a promising immunotherapeutic approach for preventing type 1 diabetes.
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PMID:Presence of diabetes-inhibiting, glutamic acid decarboxylase-specific, IL-10-dependent, regulatory T cells in naive nonobese diabetic mice. 1555 71

Immunization with autoantigenic peptides skews T cell responses in type 1 diabetes (T1D), yet the gene-expression signature characterizing this change is unclear. We used cDNA microarray technology to identify genes differentially regulated in splenocytes of T1D prone NOD mice after immunization with a disease protective glutamic acid decarboxylase 65 (GAD(65) P14) peptide. We identified 96 genes involved in cytokine secretion, humoral immune response, T cell activation, signal transduction, cell proliferation, complement activation and inflammatory responses. Up-regulation of seven chemokine and cytokine genes confirmed our previous findings of increased interferon-gamma (IFN-gamma) secretion, which may lead to a protective response in T1D. Hierarchical clustering was used to organize treated and control groups on the basis of their overall similarity in gene-expression patterns, suggesting association or co-regulation. Semi-quantitative RT-PCR was used to confirm the expression of selected genes in spleen and pancreatic draining lymph nodes. These findings can be used to compare other immunization strategies affecting the expression of these genes and explore their mechanisms of action. This microarray-based study, thus, unravels the molecular mechanism of beta-cell associated autoantigenic peptide immunization in T1D prone NOD mice, paving the way for identification of diagnostic markers and drug targets for modulating immune responses in T1D.
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PMID:Gene expression profiling in type 1 diabetes prone NOD mice immunized with a disease protective autoantigenic peptide. 1557 25

Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing beta cells in the islets of Langerhans. From studies in animal models, CD8(+) T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of beta cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8(+) clones isolated from spleens of NOD mice that had been immunized with GAD65(515-524) or insulin B-chain(15-23) peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous beta cells, they differed in the expression of IFN-gamma-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.p. injection into neonatal mice, only the insulin B-chain(15-23)-reactive CD8(+) T clone accelerated diabetes in all recipients after 4 wk, although both insulin- and GAD-reactive clones homed to pancreas and pancreatic lymph nodes with similar kinetics. Diabetes was associated with increased pancreatic T cell infiltration and, in particular, recruitment of macrophages. Thus, secretion of IFN-gamma-inducible protein-10 by autoaggressive CD8(+) lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.
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PMID:Different diabetogenic potential of autoaggressive CD8+ clones associated with IFN-gamma-inducible protein 10 (CXC chemokine ligand 10) production but not cytokine expression, cytolytic activity, or homing characteristics. 1572 83


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