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Mechanism for autoimmune dilated cardiomyopathy in PD-1-deficient mice

Research Project

Project/Area Number 13470071
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Immunology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

MINATO Nagahiro  Kyoto Univ. Grad. Sch. Biostudies Dept. Immunol. Cell Biol. Professor, 生命科学研究科, 教授 (40137716)

Co-Investigator(Kenkyū-buntansha) SHINOHARA Takashi  Kyoto Univ. Grad. Sch. Medicine Dept. Medical Chemistry Lecturer, 医学研究科, 助手 (30322770)
HONJO Tasuku  Kyoto Univ. Grad. Sch. Medicine Dept. Medical Chemistry Professor, 医学研究科, 教授 (80090504)
TANAKA Yoshimasa  Kyoto Univ. Grad. Sch. Biostudies Dept. Immunol. Cell Biol. Lecturer, 生命科学研究科, 助手 (90280700)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2002: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2001: ¥9,500,000 (Direct Cost: ¥9,500,000)
KeywordsPD-1 / PD-L1 / Negative receptors / Autojmmune diseases / Autoantibody / Antoantigen / Dilated cardiomyopathy
Research Abstract

We have reported that PD-1-deficient mice of BACB/c background develop dilated cardiomyopathy associated with the deposition of antoantibodies in cardiac muscles. In this project, we attempted to identify the autoantigen responsible for the disease. We obtained the following results.
1) We succeeded in purifying the antigen recognized by antoantibodies in the diseased mice and identified it as a heart-specific troponin I (cTnI).
2) We established monoclonal antibodies for cTnI and could show that the injection with the moAb into normal mice developed dilated cardiomyopathy indistinguishable from that in PD-1-deficient mice.
3) Anti-cTnI moAb induced voltage-dependent Ca^<2+> -influx in isolated cardiac muscle cells. These results have clearly indicated that the dilated cardiomyopathy in PD-1-deficient mice is an autoimmune disease caused by specific autoantibodies, which stimulate cardiac muscle functions. Based on the results, we have also developed a ELISA system to detect human anti-cTnI autoantibodies, which enables to screen them in human dilated cardiomyopathy patients. In addition, using a mouse model, we have indicated that PD-L1 expressed on some tumors contributes to the escape of tumor cells from host immune surveillance and injection of anti-PD-L1 in vivo induces significant therapeutic effect on the tumor growth. For the future therapeutic trial in human malignancy, we also started to produce soluble recombinant human PD-1 and PD-L1 proteins.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (16 results)

All Other

All Publications (16 results)

  • [Publications] Iwai, Y., et al.: "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade"Proc. Natl. Acd. Sci. USA. 99. 12293-12297 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida, M., et al.: "Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues"Immunol. Letters. 84. 57-62 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimura, H., et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice"Science. 291. 319-322 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwai, Y., et al.: "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade"Proc. Natl. Acd. Sci. USA. 99. 12293-12297 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishida, M., et al.: "Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues"Immunology Letters. 84. 57-62 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nishimura, H., et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice"Science. 291. 319-322 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwai, Y., et al.: "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade"Proc. Natl. Acd Sci. USA. 99. 12293-12297 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ishida, M., et al.: "Differential expression of PD-L1 and PD-L2,ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoletic tissues"Immunol. Letters. 84. 57-61 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nishimura, H., et al.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice"Science. 291. 291:319-291:322 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Katagiri, K., Hattori, M., Minato, N., Kinashi, T.: "Rap 1 functions as a key regulator of T cell and APC interactions and modulates T cell-responses"Molecular and Cellular Biology. 22. 1001-1015 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyagawa, F., Tanaka, Y., Yamashita, S., Danno, K., Uehara, B., Mikami, M., Minato, N.: "Essential contribution of germline-encoded residues in Jg1.2 segment to the recognition of nonpeptide antigens by human gd T cells."The Journal of Immunology. 167. 6773-6779 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato, Y., Tanaka, Y., Miyagawa, F., Yamashita, S., Minato, N.: "Targeting of tumor cells for human gamma delta T cells by nonpeptide antigens"The Journal of Immunology. 167. 5092-5098 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyagawa, F., Tanaka, Y., Yamashita, S., Minato, N.: "Essential reguirement of antigen presentation by monocyte-lineage cells for the activation of brimary human gd Tells by aminobisphos phonate antigen"The Journal of Immunology. 166. 5508-5514 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nishimura, H., Tanaka, Y., Okazaki, T., Nakatani, K., Hara, M., Nishio, R., Matsumori, A., Hiai, H., Minato, N., Honjo, T.: "Autoimmune dilated cardiomyopathy in PD-1 receptor deficient mice"Science. 291. 319-322 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Suga, K., Katagiri, K., Harazaki, M., Kinashi, T., Hattori, M., Minato, N.: "CD98 induces LFA-1-mediated cell adhesion in lymphoid cells via activation of"FEBS Letters. 489. 249-253 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 谷口克, 谷口維紹: "シリーズ・バイオサイエンスの新世紀第13巻 生体防御 一免疫と感染症"共立出版株式会社. 11(44~55) (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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