Induction of glutamic acid decarboxylase 65-specific Th2 cells and suppression of autoimmune diabetes at late stages of disease is epitope dependent.
Peptide-based immunotherapy is one strategy by which to selectively suppress the T cell-mediated destruction of beta cells and treat insulin-dependent diabetes mellitus (IDDM). Here, we investigated whether a panel of T cell epitopes derived from the beta cell autoantigen glutamic acid decarboxylase 65 (GAD65) differ in their capacity to induce Th2 cell function in nonobese diabetic (NOD) mice and in turn prevent overt IDDM at different preclinical stages of disease development. The panel consists of GAD65-specific peptides spanning aa 217-236 (p217), 247-265 (p247), 290-309 (p290), and 524-543 (p524). Our studies revealed that all of the peptides effectively prevented insulitis and diabetes when administered to NOD mice before the onset of insulitis. In contrast, only a mixture of p217 and p290 prevented progression of insulitis and overt IDDM in NOD mice exhibiting extensive beta cell autoimmunity. Immunization with the GAD65-specific peptides did not block IDDM development in NOD mice deficient in IL-4 expression. These findings demonstrate that GAD65-specific peptide immunotherapy effectively suppresses progression to overt IDDM, requires the production of IL-4, and is dependent on the epitope targeted and the extent of preexisting beta cell autoimmunity in the recipient.
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill 27599, USA. rmitsch@med.unc.edu
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Wang
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Serreze
D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D004338:Drug Combinations; D004790:Enzyme Induction / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000502:physiology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000096:biosynthesis* / Q000276:immunology; D007108:Immune Tolerance; D007114:Immunization; D007274:Injections, Intraperitoneal; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology; D018418:Th2 Cells / Q000201:enzymology* / Q000276:immunology; D013997:Time Factors
D001324:Autoantigens; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D005968:Glutamate Decarboxylase