4.7 Article

Targeting of pancreatic glia in type 1 diabetes

Journal

DIABETES
Volume 57, Issue 4, Pages 918-928

Publisher

AMER DIABETES ASSOC
DOI: 10.2337/db07-0226

Keywords

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Funding

  1. NCATS NIH HHS [UL1 TR000005] Funding Source: Medline
  2. NCRR NIH HHS [MO1 RR00084] Funding Source: Medline
  3. NIDDK NIH HHS [R01 DK24021] Funding Source: Medline

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OBJECTIVE - Type 1 diabetes reflects autoimmune destruction of P-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 beta 2-microglobulin (beta 2m) to pSC in NOD.beta 2m(-/-) 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 histocompatibility complex (MHC) class II and were lysed by ex vivo CTLs from diabetic NOD mice. In vivo, restoration of MHC class I in GFAP-beta 2m 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 gamma-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 P-cell demise.

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