Journal
JOURNAL OF DIABETES RESEARCH
Volume 2016, Issue -, Pages -Publisher
HINDAWI LTD
DOI: 10.1155/2016/9083103
Keywords
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Funding
- NIH Tetramer Core Facility [HHSN272201300006C]
- Iacocca Foundation
- Leona M. and Harry B. Helmsley Charitable Trust
- NIH [5F31CA162875, P30CA016087]
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Type 1 diabetes is an autoimmune disease in which insulin-producing pancreatic islet beta cells are the target of self-reactive B and T cells. T cells reactive with epitopes derived from insulin and/or IGRP are critical for the initiation and maintenance of disease, but T cells reactive with other islet antigens likely have an essential role in disease progression. We sought to identify candidate CD8(+) T cell epitopes that are pathogenic in type 1 diabetes. Proteins that elicit autoantibodies in human type 1 diabetes were analyzed by predictive algorithms for candidate epitopes. Using several different tolerizing regimes using synthetic peptides, two new predicted tolerogenic CD8(+) T cell epitopes were identified in the murine homolog of the major human islet autoantigen zinc transporter ZnT8 (aa 158-166 and 282-290) and one in a non-beta cell protein, dopamine beta-hydroxylase (aa 233-241). Tolerizing vaccination of NOD mice with a cDNA plasmid expressing full-length proinsulin prevented diabetes, whereas plasmids encoding ZnT8 and D beta H did not. However, tolerizing vaccination of NOD mice with the proinsulin plasmid in combination with plasmids expressing ZnT8 and D beta H decreased insulitis and enhanced prevention of disease compared to vaccination with the plasmid encoding proinsulin alone.
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