Targeting of pancreatic glia in type 1 diabetes.
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.
Tsui
Hubert
H
The Hospital for Sick Children, 555 University Ave., 10th Floor Elm Wing, Rm. 10126, Toronto, Ontario, M5G 1X8, Canada.
Chan
Yin
Y
Tang
Lan
L
Winer
Shawn
S
Cheung
Roy K
RK
Paltser
Geoffrey
G
Selvanantham
Thirumahal
T
Elford
Alisha R
AR
Ellis
James R
JR
Becker
Dorothy J
DJ
Ohashi
Pamela S
PS
Dosch
Hans-Michael
HM
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
D005904:Glial Fibrillary Acidic Protein; D007328:Insulin; D001613:beta 2-Microglobulin