Research of autoreactive Tcells to insulin as a major autoantigen in type 1 diabetes

• Project/Area Number: 17590932
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kobe University
• Principal Investigator: MORIYAMA Hiroaki Kobe University, Graduate School of Medicine, Research fellow (70372646)
• Co-Investigator(Kenkyū-buntansha): YOKONO Koichi Kobe University, Graduate School of Medicine, Professor (50144580) ; NAGATA Masao Kobe University, Graduate School of Medicine, Professor (70294220) ; HARA Kenta Kobe University, Graduate School of Medicine, Professor (70397826)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,550,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥150,000); Fiscal Year 2007: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Type 1 diabetes / insulin / autoreactive T cell / 自己反応性T細胞

Research Abstract

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.

Research Products

• [Journal Article] Autoreactive T cell response in CD25 negative fraction of peripheral blood mononuclear cells from establishedtype 1 diabetes (2008)
  • Author(s): Morivama, H, Kotani, R, Katsuta, A, Kameno, M, Arai, T, Okumachi, Y, Kishi, M, Yamada, K, Yasuda, H, Hara, K, Yokono, K, Nagata M
  • Journal Title: Ann N Y Acad Sci (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Intravenous Aministration of Murine Proinsulin I or 2 Expressing Fiber-mutant Recombinant Adenovirous Vector Protects Diabetes in NOD mice (2008)
  • Author(s): Yamada, K, Morivama, H, Okumachi, Y, Arai, T, Kameno, M, Kishi, M, Yasuda, H, Hara, K, Yokono, K, Naeata, M
  • Journal Title: A nn N Y Acad Sci (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Insulin as a T cell antigen in type 1 diabetes supported by the evidence from the insulin knockout NOD mice. (2007)
  • Author(s): Moriyama. H
  • Journal Title: Diabetes Res Clin Pract. 77S
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immunological aspects of fluminant type 1 diabetes (2007)
  • Author(s): Nagata M
  • Journal Title: Diabetes Res Clin Pract. S99
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Modification of the Rb-binding domain of replication-competent adenoviral vector enhances cytotoxieity against human esophageal cancers via NF-kappa B activity. (2007)
  • Author(s): Yamada K
  • Journal Title: Hum Gene Ther 18(5) Pages: 389-400
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Insulin as a T cell antigen in type 1 diabetes supported by the evidence from the insulin knockout NOD mice (2007)
  • Author(s): Morivama, H, Nagata, M., Arai, T, Okumachi, Y, Yamada, K, Kotani, R, Yasuda, H, Hara, K, Yokono, K
  • Journal Title: Diabetes Res Clin Pract 23:77S
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunological aspects of'fulminant type 1 diabetes (2007)
  • Author(s): Nagata, M, Morivama, H, Kotani, R, Yasuda, H, Kishi, M, Kurohara, M., Hara, K, Yokono, K
  • Journal Title: Diabetes Res Clin Pract
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Modification of the Rb-binding domain of replication-competent adenoviral vector enhances cytotoxicity against human esophageal cancers via NF-kappaB activity (2007)
  • Author(s): Yamada, K, Moriyama, H, Yasuda, H, Hara, IC, Maniwa, Y, Hamada, H, Yokono, K, Napata, M
  • Journal Title: Hum Gene Ther 18(5) Pages: 389-400
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Insulin as a T cell antigen in type 1 diabetes supported by the evidence from the insulin knockout NOD mice. (2007)
  • Author(s): Moriyama H
  • Journal Title: Diabetes Research & Clinical Practice 77S
• [Journal Article] Immunological Aspects of 'Fulminant Type 1 Diabetes' (2007)
  • Author(s): Nagata M
  • Journal Title: Diabetes Research & Clinical Practice 77S
• [Journal Article] Modification of the Rb-binding Domain of Replication-Competent Adenovirus Vector Enhances Cytotoxicity Against Human Esophageal Cancers via NF-κB Activity (2007)
  • Author(s): Yamada K
  • Journal Title: Human Gene Therapy 18(5) Pages: 389-400
  • Peer Reviewed
• [Journal Article] Insulin as a T cell antigen in type 1 diabetes supported by the evidence from the insulin knouckout NOD mice. (2007)
  • Author(s): Moriyama H
  • Journal Title: Diabetes Research ＆ Clinical Practice (in press)
• [Journal Article] Immunological Aspects of 'Fulminant Type 1 Diabetes' (2007)
  • Author(s): Nagata M
  • Journal Title: Diabetes Research ＆ Clinical Practice (in press)
• [Journal Article] Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions (2007)
  • Author(s): Zhou J
  • Journal Title: Kobe medical Journal (in press)
• [Journal Article] Modification of the Rb-binding Domain of Replication-Competent Adenovirus Vector Enhances Cytotoxicity Against Human Esophageal Cancers via NF-κB Activity (2007)
  • Author(s): Yamada K
  • Journal Title: Human Gene Therapy (In press)
• [Journal Article] A new model of insulin-deficient diabetes: male NOD mice with a singles copy of ins1 and no ins2 (2006)
  • Author(s): Babaya N
  • Journal Title: Diabetologia 49 Pages: 1222-8
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A new model of insulin-deficient diabetes: male NOD mice with a single copy of Ins and no Ins2 (2006)
  • Author(s): Babaya, N., Nakayama, M., Morivama. H., Gianani, R., Still, T, Miao, D., Yu, L., H utton, J.C., Eisenbarth, G.S
  • Journal Title: Diabetologia 49(6) Pages: 1222-8
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A new model of insulin-deficient diabetes : male NOD mice with a single copy of Ins1 and no Ins2. (2006)
  • Author(s): Babaya N
  • Journal Title: Diabetes 49 Pages: 1222-1228
• [Journal Article] 1型糖尿病における自己抗原反応性T細胞検出と病態におけるインスリンの役割 (2006)
  • Author(s): 森山啓明
  • Journal Title: 内分泌・糖尿病科 23 Pages: 527-533
• [Journal Article] A possible association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 gene with obesity in native Javanese in Indonesia (2005)
  • Author(s): Danawati, C. W.
  • Journal Title: Diabetes Metab Res. Rev 21 Pages: 465-469
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prime role for an insulin epitope in the deveopment of type 1 diabetes in NOD mice. (2005)
  • Author(s): Nakayama M
  • Journal Title: Nature 12 Pages: 220-3
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Interferon-α as a Mediator of Polyinosinic: Polycytidylic Acid-Induced Type 1 Diabetes. (2005)
  • Author(s): Devendra, D
  • Journal Title: Diabetes 54 Pages: 2549-2556
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A possible association of ProI2Ala polymorphism in peroxisome proliferator-activated receptor gamma2 gene with obesity in native Javanese in Indonesia (2005)
  • Author(s): Danawati, C. W., Nagata, M., Moriyama, H., Hara, K., Yasuda, H., Nakayama, M., Kotani, R., Yamada, K., Sakata, M., Kurohara, M., Wiyono, P., Asdie, H., Sakaue, M., Taniguchi, H., Yokono. K
  • Journal Title: Diabetes Metab Res 21 Pages: 465-469
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice (2005)
  • Author(s): Nakayama, M, Abiru, N, Morivama, H, Babaya, N, Liu, E, Miao, D, Yu, L, Wegmann, DR, Hutton, JC, Elliott, JF, Eisenbarth, GS
  • Journal Title: Nature 12;435(7039) Pages: 20-3
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon-{alpha} as a Mediator of Polyinosinic:Polycytidylic Acid-Induced Type 1 Diabetes (2005)
  • Author(s): Devendra, D., Jasinski, J., Melanitou, E., Nakayama, M., Li, M., Hensley, B., Paronen, J., Morivama, H., Miao, D., Eisenbarth, G S., Liu, E
  • Journal Title: Diabetes 54 Pages: 2549-2556
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon-α as a Mediator of Polyinosinic : Polycytidylic Acid-Induced Type 1 Diabetes. (2005)
  • Author(s): Devendra D
  • Journal Title: Diabetes 54 Pages: 2549-2556
• [Journal Article] Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. (2005)
  • Author(s): Nakayama M
  • Journal Title: Nature 435 Pages: 220-223
• [Journal Article] 1型糖尿病における自己反応性T細胞 (2005)
  • Author(s): 森山 啓明
  • Journal Title: 臨床免疫 44 Pages: 141-147
• [Journal Article] A possible association of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma2 gene with obesity in native Javanese in Indonesia (2005)
  • Author(s): Danawati CW
  • Journal Title: Diabetes Metab Res.Rev. 21 Pages: 465-469
• [Journal Article] Autoreactive T cell response in CD25 negative fraction of peripheral blood mononuclear cells from established type 1 diabetes
  • Author(s): Moriyama H
  • Journal Title: Ann NY Acad Sci. (in press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Intravenous administration of murine proinsulin 1 or 2 expressing fiber-mutant recombinant adenovirus vectors protects diabtes in NOD mice
  • Author(s): Yamada K
  • Journal Title: Ann NY Acad Sci. (in press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Presentation] Autoreactive T cell responses in CD25 negative fraction of peripheral blood mononuclear cells from established type 1 diabetes. (2007)
  • Author(s): Moriyama H
  • Organizer: the 9th International Congress of the immunology of Diabetes Society and American Diabetes Association Research Symposium
  • Place of Presentation: 米国 マイアミ
  • Year and Date: 2007-11-15
• [Presentation] One amino acid difference of insulin:9-23 peptides critically influence on the effect of deletional therapy for experimental autoimmune diabetes(EAD). (2007)
  • Author(s): Okumachi Y.
  • Organizer: the 9th International Congress of the immunology of Diabetes Society and American Diabetes Association Research Symposium
  • Place of Presentation: 米国 マイアミ
  • Year and Date: 2007-11-15
• [Presentation] Intervenous administration of murine proinsulin1 or 2 expressing recombinant adenovirus vector protects from diabetes in NOD mice. (2007)
  • Author(s): Yamada K.
  • Organizer: the 9th International Congress of the immunology of Diabetes Society and American Diabetes Association Research Symposium
  • Place of Presentation: 米国 マイアミ
  • Year and Date: 2007-11-15
• [Presentation] Autoreactive T cell responses in CD25 negative fraction of peripheral blood mononuclear cells from established type 1 diabetes (2007)
  • Author(s): Morivama, H., Kotani, R., Kameno, M., Arai, T, Okumachi, Y., Kishi, M., Kurohara, M, Yasuda, H., Yamada, K., Yokono, K, Nagata M
  • Organizer: the 9th International Congress of the immunology of Diabetes Society and American Diabetes Association Research (IDS-9)
  • Place of Presentation: Miami, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] One amino acid difference of insulin:9-23 peptides critically influence on the effect of deletional therapy for experimental autoimmune diabetes (EAD). Acta Diabetologia Vol. 44, S36 Poster presentation at the 9°i International Congress of the immunology of Diabetes Society and American Diabetes Association Research Symposium at Miami, November 2007 (2007)
  • Author(s): Okumachi, Y., Moriyama, H., Kameno, M., Arai, T, Kishi, M., Kurohara, M, Yamada, K., Yasuda, H., Yokono, K., Nagata, M
  • Organizer: the 9th International Congress of the immunology of Diabetes Society and American Diabetes Association Research (IDS-9)
  • Place of Presentation: Miami, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Intervenous administration of murine proinsulinl or 2 expressing recombinant adenovirus vector protects from diabetes in NOD mice. Acta Diabetologia Vol. 44, S56 Poster presentation at the 9'" International Congress of the immunology of Diabetes Society and American Diabetes Association Research Symposium at Miami, November 2007 (2007)
  • Author(s): Yamada, K., Morivama, H., Arai, T, Kameno, M., Okumachi, Y, Kishi, M., Kurohara, M, Yasuda, H., Yokono, K, Napata, M
  • Organizer: the 9°th International Congress of the immunology of Diabetes Society and American Diabetes Association Research (IDS-9)
  • Place of Presentation: Miami, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Subcutaneous transplantation with Proinsulin2 expressing fibroblasts protects diabetes in NOD mice (2006)
  • Author(s): Yamada, K., Moriyama, H., Okumachi, Y, Arai, T., Kishi, M., Kurohara, M., Yasuda, H., Hara, K, Yokono, K., Nagata, M
  • Organizer: the 66th American Diabetes Association (ADA) meeting
  • Place of Presentation: Washington DC, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Intravenous Administration of Insulinl B9-23 Peptide Reduces T Cell Reactivity to Insulin and Protects Autoimmune Diabetes in Experimental Autoimmune Diabetes (2006)
  • Author(s): Okumachi, Y, Morivama, H., Arai, T., Kishi, M., Kurohara, M., Yasuda, H., Kotani, R., Yasuda, H., Hara, K., Yokono, K., Nagata, M
  • Organizer: the 66th American Diabetes Association (ADA) meeting
  • Place of Presentation: Washington DC, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Insulin reactive T cells in EAD (Exprimental Autoimmune Diabetes) Model (2005)
  • Author(s): Moriyama H
  • Organizer: The 8th meeting of the Immunology of Diabetes Society
  • Place of Presentation: Awaji Island, Japan
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Insul in as aT cell antigen (2005)
  • Author(s): Moriyama H
  • Organizer: The 13th Korean-Japan Symposium of Diabetes Mellitus
  • Place of Presentation: Seoul, Korea
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Autoreactive T cell responses in CD25 negative fraction of peripheral blood mononuclear cells from established type 1 diabetes (2005)
  • Author(s): Moriyama H
  • Organizer: The 9th meeting of the Immunology of Diabetes Society
  • Place of Presentation: Miami, USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Insulin as a primary autoantigen: Evidence from dual NOD insulin gene knockouts. Endocrine Journal Vol.52 Suppl. 23. Symposium in the 8th Meeting of the Immunology of Diabetes Society (IDS-8), October 2005 (2005)
  • Author(s): Nakayama, M, Abiru, N, Morivama, H, Babaya, N, Liu, E, Miao, D, Yu, L, Eisenbarth, GS
  • Organizer: the 8th Meeting of the Immunology of Diabetes Society (DS-8)
  • Place of Presentation: Awaji Island
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Insulin reactive T cells in EAD(Exprimental Autoimmune Diabetes) Model (2005)
  • Author(s): Moriyama, H, Nagata, M, Kotani, R, Okumachi, Y, Arai, T, Yamada, K, Yasuda, H, Eisenbarth, GS, Yokono, K
  • Organizer: the 8th Meeting of the Immunology of Diabetes Society (IDS-8)
  • Place of Presentation: Awaji Island
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Insulin as a T cell antigen (2005)
  • Author(s): Morivama, H
  • Organizer: the 13th Korean-Japan Symposium of Diabetes Mellitus
  • Place of Presentation: Seoul, Korea
  • Description: 「研究成果報告書概要(欧文)」より