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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Original Articles|
December 01 1994
Immunization With the Larger Isoform of Mouse Glutamic Acid Decarboxylase (GAD67) Prevents Autoimmune Diabetes in NOD Mice
John F Elliott;
John F Elliott
Departments of Immunology Medical Microbiology and Infectious Diseases, University of Alberta
Edmonton, Alberta
Department of Microbiology and Immunology, University of Western Ontario and the Robarts Research Institute
London, Ontario, Canada
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Hui-Yu Qin;
Hui-Yu Qin
Departments of Immunology Medical Microbiology and Infectious Diseases, University of Alberta
Edmonton, Alberta
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Siinita Bhatti;
Siinita Bhatti
Department of Microbiology and Immunology, University of Western Ontario and the Robarts Research Institute
London, Ontario, Canada
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Dean K Smith;
Dean K Smith
Departments of Immunology Medical Microbiology and Infectious Diseases, University of Alberta
Edmonton, Alberta
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Raj Kumari Singh;
Raj Kumari Singh
Department of Microbiology and Immunology, University of Western Ontario and the Robarts Research Institute
London, Ontario, Canada
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Tom Dillon;
Tom Dillon
Departments of Immunology Medical Microbiology and Infectious Diseases, University of Alberta
Edmonton, Alberta
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Jana Lauzon;
Jana Lauzon
Departments of Immunology Medical Microbiology and Infectious Diseases, University of Alberta
Edmonton, Alberta
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Bhagirath Singh
Bhagirath Singh
Departments of Immunology Medical Microbiology and Infectious Diseases, University of Alberta
Edmonton, Alberta
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Address correspondence and reprint requests to Dr. Bhagirath Singh, Department of Microbiology and Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Diabetes 1994;43(12):1494–1499
Article history
Received:
May 05 1993
Revision Received:
August 16 1994
Accepted:
August 16 1994
PubMed:
7525393
Citation
John F Elliott, Hui-Yu Qin, Siinita Bhatti, Dean K Smith, Raj Kumari Singh, Tom Dillon, Jana Lauzon, Bhagirath Singh; Immunization With the Larger Isoform of Mouse Glutamic Acid Decarboxylase (GAD67) Prevents Autoimmune Diabetes in NOD Mice. Diabetes 1 December 1994; 43 (12): 1494–1499. https://doi.org/10.2337/diab.43.12.1494
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