UMLS:C0751781 - FACTA Search

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Query: UMLS:C0751781 (NOD)
6,696 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 65-kDa isoform of glutamic acid decarboxylase (GAD65) has been implicated in autoimmune diabetes in NOD mice, but the role of the 67-kDa GAD isoform (GAD67) is less clear. We found that immunization of 4-week-old NOD mice with purified recombinant mouse GAD67 prevented or significantly delayed the onset of diabetes. To further explore this phenomenon, we characterized anti-GAD67 immune responses in naive and GAD-immunized NOD mice. Anti-GAD67 antibodies titers were relatively low in naive mice at all ages, but a single immunization with GAD67 at 4 weeks induced high titers of anti-GAD antibodies by 6 weeks of age. In both 4-week-old and diabetic NOD mice, there were significant endogenous T-cell proliferative responses against purified recombinant mouse GAD67. These T-cell proliferative responses were blocked by anti-I-ANOD and anti-CD4 antibodies. To characterize the anti-GAD T-cell responses in the NOD mice, we established T-cell lines and T-cell clones which recognized GAD67, and we used recombinant subfragments of GAD to localize the predominant T-cell epitopes in GAD67. T-cells from naive NOD mice proliferated in response to all GAD subfragments, whereas T-cells from diabetic mice responded primarily to the COOH-terminal 83 amino acids of GAD67. These results suggest that GAD67 is an autoantigen in IDDM and immunization of prediabetic NOD mice with GAD67 can prevent the onset of diabetes.
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PMID:Immunization with the larger isoform of mouse glutamic acid decarboxylase (GAD67) prevents autoimmune diabetes in NOD mice. 752 93

Type 1 diabetes in man and the NOD (H-2g7) mouse is frequently associated with an autoimmune response to two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. GAD-specific autoantibodies produced by B cells and GAD-specific T cells have been observed in both species. In the current study, the response to a GAD65-derived peptide, GAD65 524-543, previously reported to be an epitope recognized by spleen cells obtained from 3-week-old NOD mice, was assessed in NOD MHC and non-MHC congenic strains. Although spontaneous reactivity to GAD65 524-543 was not observed in NOD mice, the peptide was immunogenic in NOD mice as well as in two NOD congenic strains which are both H-2g7, B10.H-2g7 and NOD.B6Il2-Tshb. This was surprising since the B10.H-2g7 strain does not develop diabetes or insulitis and fewer than 3% of NOD.B6Il2-Tshb mice develop diabetes. The response to GAD65 524-543 was shown to be controlled by the MHC since neither the B10 nor the NOD.H-2b strain, both of which are H-2b, responded to the peptide. This study demonstrates that T cell responsiveness to GAD-derived peptides can be elicited in strains of mice that are resistant to the development of spontaneous diabetes, suggesting that peripheral tolerance to GAD is not associated with protection from diabetes.
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PMID:Responses of NOD congenic mice to a glutamic acid decarboxylase-derived peptide. 784 Aug 55

To test the role of glutamic acid decarboxylase (GAD65) or bovine serum albumin (BSA) autoimmunity in the pathogenesis of diabetes, GAD65 or BSA was injected intraperitoneally into neonatal female NOD mice (100 micrograms/mouse of each protein). Treatment with GAD65, but not with BSA, significantly delayed the onset of diabetes compared with control mice (P < 0.05). At 18 weeks, 6 of 10 control mice compared with 0 of 10 GAD65-treated mice (P = 0.005) and 7 of 14 BSA-treated mice had developed diabetes. However, after 79 weeks, 6 of 10 of the GAD65-treated mice were diabetic compared with 9 of 10 of the control mice and 12 of 14 of the BSA-treated mice. In GAD65-treated mice without diabetes, insulitis was markedly reduced compared with control or BSA-treated mice (P < 10(-4)). To further elucidate why GAD becomes an autoantigen, the expression in NOD mice islets was studied. Quantitative immunohistochemistry revealed that islet cell expression of GAD was increased in 5-week-old NOD mice compared with BALB/c mice (P = 0.02). With the occurrence of insulitis (9-15 weeks), the GAD expression was further increased relative to 5-week-old NOD mice (P < 0.02). In conclusion, GAD, but not BSA, autoimmunity is important for the development of diabetes in NOD mice. Furthermore, concordant with the appearance of insulitis, the GAD expression increased in NOD mouse islets, which could possibly potentiate the beta-cell-directed autoimmunity.
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PMID:Neonatal tolerization with glutamic acid decarboxylase but not with bovine serum albumin delays the onset of diabetes in NOD mice. 795 2

The 12th International Immunology of Diabetes Workshop was held during April 1993 in Orlando, Florida, to review research progress since the 11th Immunology of Diabetes Workshop meeting in Nagasaki, Japan, one and a half years before. The NOD mouse may have as many as 10 susceptibility genes, including its novel IA major histocompatibility complex antigen and a defective interferon-gamma receptor, whereas human IDDM is so far known to be encoded by cis and trans complementation products of certain DQ genes on chromosome 6q, and a gene in the insulin-like growth factor II region on chromosome 11p. A unique protein regulator of the X box promotor of the highly susceptible DQB1*0302 allele has also been found. Islet cell antibody negative siblings of IDDM patients appear to have lower than expected abilities to secrete insulin in response to intravenous glucose. Sera from patients before and/or after developing IDDM immunoprecipitate two native proteins of 64,000- and 38,000-M(r) glutamic acid decarboxylase (GAD65) reacting to conformational epitopes. However, a multitude of other autoantibodies often reacting to denatured proteins through linear epitopes have also been identified. The first workshop for GAD antibody assays was successfully completed; however, the 38,000-M(r) antigen has not yet been identified. Other autoantibodies reactive to gangliosides and to sulfatides continue to be reported. Insulitis has come to be recognized as a sometimes protective event. Protective insulitis predominates in older lesions. It can be induced by as disparate means as tuberculin antigen administration, by interleukin-4 treatments, by transfer of T-cell lines generated in autologous mixed lymphocyte responses, and by immunization to insulin B-chain, whereas oral islet cell antigens, such as insulin, can delay diabetes onset in the NOD mouse.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The 12th International Immunology and Diabetes Workshop. Orlando, Florida. 810 Jul 86

GAD is a major islet cell autoantigen in human type 1 diabetes mellitus. Autoantibodies are preferentially directed against the 65-kD isoform of the enzyme which is the only form expressed in human islets of Langerhans. The NOD mouse is a spontaneous model of type 1 diabetes, frequently employed in studies dealing with the immunopathogenesis of the disease. In the present study the reactivity of sera from 34 prediabetic and 15 diabetic NOD mice was tested against GAD protein present in islets of Langerhans and cerebellum, and against recombinant, semi-purified GAD-65 and GAD-67. A rabbit antiserum (K2) raised against GAD-67 could readily recognize the recombinant GAD-67 and the isoform present in rat and mouse islets and mouse brain. A MoAb (GAD-6) specific for the GAD-65 isoform reacted against the recombinant GAD-65 and the isoform present in rat islets and mouse brain, whereas no reactivity was observed when using mouse islets. However, when testing the NOD mice sera by immunohistochemistry, immunoprecipitation and Western blot, no reactivity against any of the isoforms of GAD could be detected. Using reverse transcription polymerase chain reaction (PCR), GAD-67 mRNA could be detected in mouse and rat islets and in mouse brain. GAD-65 mRNA could also be detected in rat islets and mouse brain, but apparently a much lower copy number is present in mouse islets. These findings stress important differences in the immune response occurring in the animal model NOD mouse compared with human type 1 diabetes, and emphasize that human and animal type 1 diabetes possibly represent the final outcome of several different etiological factors.
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PMID:Absence of autoantibodies against glutamate decarboxylase (GAD) in the non-obese diabetic (NOD) mouse and low expression of the enzyme in mouse islets. 814 57

The autoimmune response that leads to destruction of pancreatic islet beta-cells and insulin-dependent diabetes mellitus (IDDM) has a genetic basis; however, environmental factors can exert profound modulating effects on the genetic predisposition to this autoimmune response. Recent studies in animal models for human IDDM, the genetically diabetes-prone NOD mouse and BB rat, have revealed that microbial agents--including certain viruses and extracts of bacteria, fungi, and mycobacteria--often have a protective action against diabetes development. Many of these microbial preparations are immune adjuvants, which are agents that stimulate the immune system. The protective effects of these agents against diabetes appear to involve perturbations in the production of cytokines, which are polypeptides produced by and acting on cells of the immune system. Thus, recent studies in NOD mice suggest that the islet beta-cell-directed autoimmune response may be mediated by a T-helper 1 (Th1) subset of T-cells producing the cytokines interleukin-2 (IL-2) and interferon-gamma. These studies also suggest that the diabetes-protective effects of administering microbial agents, adjuvants, and a beta-cell autoantigen (GAD65 [glutamic acid decarboxylase]) may result from activation of a Th2 subset of T-cells that produce the cytokines IL-4 and IL-10 and consequently downregulate the Th1-cell-mediated autoimmune response. The clinical implication of these findings is that the autoimmune response leading to islet beta-cell destruction and IDDM may be amenable to prevention or suppression by therapeutic interventions aimed at stimulating the host's own immunoregulatory mechanisms.
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PMID:Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation? 778 55

We previously demonstrated that a spontaneous Th1 response against glutamate decarboxylase (GAD65) arises in NOD mice at four weeks in age and subsequently T cell autoimmunity spreads both intramolecularly and intermolecularly. Induction of passive tolerance to GAD65, through inactivation of reactive T cells before the onset of autoimmunity, prevented determinant spreading and the development of insulin-dependent diabetes mellitus (IDDM). Here, we examined whether an alternative strategy, designed to induce active tolerance via the engagement of Th2 immune responses to GAD65, before the spontaneous onset of autoimmunity, could inhibit the cascade of Th1 responses that lead to IDDM. We observed that a single intranasal administration of GAD65 peptides to 2-3-wk-old NOD mice induced high levels of IgG1 antibodies to GAD65. GAD65 peptide treated mice displayed greatly reduced IFN gamma responses and increased IL-5 responses to GAD65, confirming the diversion of the spontaneous GAD65 Th1 response toward a Th2 phenotype. Consistent with the induction of an active tolerance mechanism, splenic CD4+ (but not CD8+) T cells from GAD65 peptide-treated mice, inhibited the adoptive transfer of IDDM to NOD-scid/scid mice. This active mechanism not only inhibited the development of proliferative T cell responses to GAD65, it also limited the expansion of autoreactive T cell responses to other beta cell antigens (i.e., determinant spreading). Finally, GAD65 peptide treatment reduced insulitis and long-term IDDM incidence. Collectively, these data suggest that the nasal administration of GAD65 peptides induces a Th2 cell response that inhibits the spontaneous development of autoreactive Th1 responses and the progression of beta cell autoimmunity in NOD mice.
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PMID:Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. 866 14

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

Two homozygous lines of transgenic NOD/Lt mice expressing MHC class II I-E molecules at quantitatively different levels were utilized to study mechanisms of I-E-mediated diabetes prevention. In line 12, I-E expression on APC at levels comparable with that in BALB/cByJ controls conferred only partial diabetes resistance. In line 5, greater than normal I-E levels on APC correlated with nearly complete resistance. Levels of endogenously encoded I-Ag7 correlated inversely with transgene-induced I-E expression. T cell transfer experiments into NOD/severe combined immunodeficient mice demonstrated the presence of pathogenic T cells in I-E+ donors, and that continuous expression of I-E on hemopoietically derived APC was required to block their pathogenic function. T cells from transgenic and nontransgenic NOD/Lt mice primed in vivo against the beta cell autoantigen 65-kDa isoform of glutamic acid decarboxylase (GAD65) and two peptides derived from this protein proliferated when restimulated in vitro. However, reverse-transcription PCR and ELISA measurements of cytokine mRNA and protein levels showed that the GAD65-reactive T cells from both line 5 and line 12 mice produced higher levels of IL-4 and lower levels of IFN-gamma than similar T cells from standard NOD/Lt mice. Thus, the inverse relationship between I-E and I-Ag7 expression was associated with qualitative differences in T cell responses to putative beta cell autoantigens. Collectively, these data indicate quantitative increases in I-E expression on APC may block insulin-dependent diabetes mellitus by altering the balance of cytokines produced by beta cell autoreactive T cells.
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PMID:Quantitative thresholds of MHC class II I-E expressed on hemopoietically derived antigen-presenting cells in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection. 875 36

Human epidemiological studies delineated early exposure to intact dietary protein (e.g., most infant formulas) as an environmental risk factor for the development of IDDM. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR), an international IDDM prevention trial, has been designed to determine if avoidance of intact dairy protein in high-risk infants < or =6 months of age can reduce the subsequent diabetes incidence. We here studied the casein hydrolysate-based trial diet (Nutramigen) in NOD mice. When given either continuously or for 10 weeks after weaning, the test diet was highly effective in preventing autoimmune diabetes (32-week incidence: 4.6 vs. 58.8%) and in preserving pancreatic insulin levels, with little effect on islet inflammation. Spleen cells from protected NOD mice failed to adoptively transfer diabetes into irradiated syngeneic recipients. When co-transferred with splenocytes from diabetic donors, cells from diet-protected mice inhibited adoptive diabetes transfer (incidence 50 vs. 94%, P < 0.001). T-cell reactivity to the islet cell autoantigens ICA69 (islet cell antigen 69) and GAD65 developed only in diabetic recipients of spleen cell grafts, indicating that diabetes protection extends to more than one autoantigen. In protected mice, ICA69 T-cell reactivity was not detectable spontaneously nor after priming with this autoantigen; however, priming with the cross-reactive non-self-antigen bovine serum albumin recruited T-cells responsive to ICA69. Thus, diabetes prevention with the clinical trial diet is effective in NOD mice, where it affects some T-cell repertoires and allows development of regulatory cells that interfere with destructive autoimmunity.
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PMID:Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow's milk-based IDDM prevention trial. 907 94

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