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Targeting of Pancreatic Glia in Type 1 Diabetes

¹Research Institute, The Hospital for Sick Children, Departments of Pediatrics, Immunology and Genetics, University of Toronto, Toronto, ON, M5G 1X8, Canada
²Department of Pediatrics, Children's Hospital and University of Pittsburgh, Pittsburgh, PA, USA
³The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, ON, M5G 2C1, Canada

Objective: Type 1 Diabetes (T1D) reflects autoimmune-destruction of β-cells and peri-islet Schwann cells (pSC) 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 CTL assays in NOD mice. Cognate interaction between pSC and CD8⁺ T cells was assessed by transgenic restoration of β2-microglobulin (β 2m) to pSC in NOD.β 2m^–/– congenics. I-A^g7 and K^d epitopes in the pSC antigen GFAP were identified by peptide mapping or algorithms, respectively and the latter tested by immunotherapy.

Results: pSC cultures did not express MHC class II and were lysed by ex vivo CTLs from diabetic NOD mice. In vivo, restoration of MHC class I in GFAP-β 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 wk of age, with proliferative responses peaking around weaning and detectable life-long. Several were also recognized by T cells from new-onset T1D patients. NOD mouse immunotherapy at 8 wk with the CD8⁺ T cell epitope, GFAP79-87 but not 253-261, significantly inhibited T1D and was associated with reduced IFN- production to whole protein GFAP.

Conclusions: Collectively, these findings elucidate a role for pSC specific CD8⁺ T cells in islet inflammation and T1D pathogenesis, further supporting neuronal involvement in β-cell demise.

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