Therapeutic alteration of insulin-dependent diabetes mellitus progression by T cell tolerance to glutamic acid decarboxylase 65 peptides in vitro and in vivo.
We have reported previously that nonobese diabetic (NOD) fetal pancreas organ cultures lose the ability to produce insulin when maintained in contact with NOD fetal thymus organ cultures (FTOC). Initial studies indicated that exposure to glutamic acid decarboxylase (GAD65) peptides in utero resulted in delay or transient protection from insulin-dependent diabetes mellitus (IDDM) in NOD mice. We also found that exposure of young adult NOD mice to the same peptides could result in acceleration of the disease. To more closely examine the effects of early and late exposure to diabetogenic Ags on T cells, we applied peptides derived from GAD65 (GAD AA 246-266, 509-528, and 524-543), to our "in vitro IDDM" (ivIDDM) model. T cells derived from NOD FTOC primed during the latter stages of organ culture, when mature T cell phenotypes are present, had the ability to proliferate to GAD peptides. ivIDDM was exacerbated under these conditions, suggesting that GAD responsiveness correlates with the ivIDDM phenotype, and parallels the acceleration of IDDM we had seen in young adult NOD mice. When GAD peptides were present during the initiation of FTOC, GAD proliferative responses were inhibited, and ivIDDM was reduced. This result suggests that tolerance to GAD peptides may reduce the production of diabetogenic T cells or their capacity to respond, as suggested by the in utero therapies studied in NOD mice.
Wilson
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SS
Department of Microbiology and Immunology, University of Arizona, Tucson, AZ 85724, USA.
White
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TC
DeLuca
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D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control*; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005333:Fetus; D005968:Glutamate Decarboxylase / Q000008:administration & dosage* / Q000276:immunology* / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects*; D007115:Immunization Schedule; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000008:administration & dosage* / Q000276:immunology* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology* / Q000494:pharmacology; D011247:Pregnancy; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D007527:Isoenzymes; D010446:Peptide Fragments; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2