Targeting of pancreatic glia in type 1 diabetes.
Diabetes
; 57(4): 918-28, 2008 Apr.
Article
en En
| MEDLINE
| ID: mdl-18198358
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. RESEARCH DESIGN ANDMETHODS:
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diabetes Mellitus Tipo 1
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Diabetes
Año:
2008
Tipo del documento:
Article
País de afiliación:
Canadá