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*
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599; and
The Jackson Laboratory, Bar Harbor, ME 04609
Peptide-based immunotherapy is one strategy by which to selectively
suppress the T cell-mediated destruction of 
cells and treat
insulin-dependent diabetes mellitus (IDDM). Here, we investigated
whether a panel of T cell epitopes derived from the 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 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 cell autoimmunity in
the recipient.
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