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Identification of Novel HLA-A*0201–Restricted Epitopes in Recent-Onset Type 1 Diabetic Subjects and Antibody-Positive Relatives

¹ Benaroya Research Institute at Virginia Mason, Seattle, Washington
² Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, Child and Family Research Institute, and University of British Columbia, Vancouver, British Columbia, Canada
³ Department of Pediatrics, British Columbia Children’s Hospital, Child and Family Research Institute, and University of British Columbia, Vancouver, British Columbia, Canada
⁴ Department of Pediatrics, University of Washington, Seattle, Washington

Address correspondence and reprint requests to Nathan E. Standifer, Benaroya Research Institute at Virginia Mason, 1201 Ninth Ave., Room 260, Seattle WA, 98101. E-mail: nstand{at}benaroyaresearch.org

Abbreviations: Ab, antibody; BIMAS, BioInformatics and Molecular Analysis Section; CTL, cytotoxic T-lymphocyte; ELISpot, enzyme-linked immunospot; GFAP, glial fibrillary acidic protein; IA-2, insulinoma-associated antigen 2; IGRP, islet-specific glucose-6-phosphatase catalytic subunit–related protein; ppIAPP, prepro-islet amyloid polypeptide; PBMC, peripheral blood mononuclear cell

Cytotoxic T-lymphocytes (CTLs) are considered to be essential for ß-cell destruction in type 1 diabetes. However, few islet-associated peptides have been demonstrated to activate autoreactive CTLs from type 1 diabetic subjects. In an effort to identify novel epitopes, we used matrix-assisted algorithms to predict peptides of glial fibrillary acidic protein (GFAP), prepro-islet amyloid polypeptide (ppIAPP), and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) that likely bind to HLA-A*0201 with a strong affinity and contain a COOH-terminal proteasomal cleavage site. Seven peptides stabilized HLA-A*0201 expression in binding assays and were used to stimulate peripheral blood mononuclear cells and were evaluated for granzyme B secretion. We found that 5 of 13 type 1 diabetic subjects and 4 of 6 antibody-positive relatives exhibited greater numbers of granzyme B–secreting cells in response to at least one putative epitope compared with healthy control subjects. The most prevalent responses in antibody-positive and type 1 diabetic subjects were to ppIAPP(9-17). Other peptides recognized by type 1 diabetic or antibody-positive subjects included GFAP(143-151), IGRP(152-160), and GFAP(214-222). These data implicate peptides of ppIAPP, GFAP, and IGRP as CTL epitopes for a heterogenous CD8⁺ T-cell response in type 1 subjects and antibody-positive relatives.

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