title: Targeting of pancreatic glia in type 1 diabetes.
abstract: OBJECTIVE
  Type 1 diabetes reflects autoimmune destruction of beta-cells and peri-islet Schwann cells (pSCs), but the mechanisms of pSC death and the T-cell epitopes involved remain unclear.
  
  
  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 beta2-microglobulin (beta2m) to pSC in NOD.beta2m(-/-) 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-beta2m 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 beta-cell demise.
authors.affiliation: The Hospital for Sick Children, 555 University Ave., 10th Floor Elm Wing, Rm. 10126, Toronto, Ontario, M5G 1X8, Canada.
authors.forename: Hubert
authors.initials: H
authors.lastname: Tsui
authors.forename: Yin
authors.initials: Y
authors.lastname: Chan
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.forename: Roy K
authors.initials: RK
authors.lastname: Cheung
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Paltser
authors.forename: Thirumahal
authors.initials: T
authors.lastname: Selvanantham
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: James R
authors.initials: JR
authors.lastname: Ellis
authors.forename: Dorothy J
authors.initials: DJ
authors.lastname: Becker
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Dosch
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010060:Ovulation; D012583:Schwann Cells / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007328:Insulin; D001613:beta 2-Microglobulin