Targeting of pancreatic glia in type 1 diabetes

Abstract

OBJECTIVE-Type 1 diabetes reflects autoimmune destruction of β-cells and peri-islet Schwann cells (pSCs), but the mechanisms of pSC death and the T-cell epitopes involved remain unclear. RESEARCH DESIGN AND METHODS-Primary pSC cultures were generated and used as targets in cytotoxic T-lymphocyte (CTL) assays in NOD mice. Cognate interaction between pSC and CD8 + T-cells was assessed by transgenic restoration of β2-microglobulin β2m) to pSC in NOD.β2m) -/- congenics. I-A g7 and K d epitopes in the pSC antigen glial fibrillary acidic protein (GFAP) were identified by peptide mapping or algorithms, respectively, and the latter tested by immunotherapy. RESULTS-pSC cultures did not express major histocompati-bility complex (MHC) class II and were lysed by ex vivo CTLs from diabetic NOD mice. In vivo, restoration of MHC class I in GFAP-p2m transgenics significantly accelerated adoptively transferred diabetes. Target epitopes in the pSC autoantigen GFAP were mapped to residues 79-87 and 253-261 for K d and 96-110, 116-130, and 216-230 for I-A g7. These peptides were recognized spontaneously in NOD spleens as early as 2.5 weeks of age, with proliferative responses peaking around weaning and detectable lifelong. Several were also recognized by T-cells from new-onset type 1 diabetic patients. NOD mouse immunotherapy at 8 weeks with the CD8 + T-cell epitope, GFAP 79-87 but not 253-261, significantly inhibited type 1 diabetes and was associated with reduced γ-interferon production to whole protein GFAP. CONCLUSIONS-Collectively, these findings elucidate a role for pSC-specific CD8 + T-cells in islet inflammation and type 1 diabetes pathogenesis, further supporting neuronal involvement in β-cell demise. © 2008 by the American Diabetes Association.