Research Project
Grant-in-Aid for Scientific Research (C)
I have been studying β cell destruction by autoimmune T cells in type1 diabetes (T1D). Insulin is an important candidate molecule for the target and we have developed unique T1D mouse models related to insulin (insulin knockout NOD mice and insulin peptide induced experimental autoimmune in non-diabetes mice with the co-stimulatory molecule B7.1 in their islets; EAD model).Mice have two insulin and ins1 differs ins2 by 2 amino acid of B chain including B9. In the islet-infiltrating cells of ins2KO-NOD mice (accelerated diabetes), IFN-γ producing T cells to ins1 or 2B9-23 were predominantly observed among the epitopes recognized by CD4 T cells. This response was sequence dependent because of marked reduction of the response with an amino acid modification (Tyrosine to Alanine at position16). As for response to CD8 epitopes, the response to IGRP206-214 but not insB15-23 was predominant. IGRP is a new β cell autoantigen recognized CD8 T cells.In EAD model, ins1B9-23 immunization induced diabetes slightly accelerated than ins2B:9-23 with higher insulin autoantibody expression. Other antigenic peptides such as GAD524-543 could not induce diabetes but IGRP206-214 could induce diabetes equally well to ins1B9-23. Taken together, our study indicated that insB9-23 and IGRP206.214 are immune-dominant in T1D models.Deletional therapy for autoreactive T cells would be a strategy for antigen specific therapy in T1D. Intravenous injections of ins1 or 2B9.23 in young NOD mice did not affect diabetes. Of note, the same protocol with ins1B9-23 delayed the diabetes in the ins1B9-23 induced EAD with reduction of insulitis and insulin autoantibodies expression. Interestingly, intravenous administration of ins2B9-23 delayed the development of diabetes in both ins1EAD and ins2EAD whereas ins1B9-23 delayed diabetes in ins1EAD but not ins2EAD, suggesting that one amino acid difference gives critical influence on the effect of intravenous injection of antigenic peptide for type1 diabetes.
All 2008 2007 2006 2005 Other
All Journal Article (31 results) (of which Peer Reviewed: 8 results) Presentation (14 results)
Ann N Y Acad Sci (in press)
A nn N Y Acad Sci (in press)
Diabetes Res Clin Pract. 77S
Diabetes Res Clin Pract. S99
Hum Gene Ther 18(5)
Pages: 389-400
Diabetes Res Clin Pract 23:77S
Diabetes Res Clin Pract
Diabetes Research & Clinical Practice 77S
Human Gene Therapy 18(5)
Diabetes Research ＆ Clinical Practice (in press)
Kobe medical Journal (in press)
Human Gene Therapy (In press)
Diabetologia 49
Pages: 1222-8
Diabetologia 49(6)
Diabetes 49
Pages: 1222-1228
内分泌・糖尿病科 23
Pages: 527-533
Diabetes Metab Res. Rev 21
Pages: 465-469
Nature 12
Pages: 220-3
Diabetes 54
Pages: 2549-2556
Diabetes Metab Res 21
Nature 12;435(7039)
Pages: 20-3
Nature 435
Pages: 220-223
臨床免疫 44
Pages: 141-147
Diabetes Metab Res.Rev. 21
Ann NY Acad Sci. (in press)
