Mechanism for autoimmune dilated cardiomyopathy in PD-1-deficient mice
| Project/Area Number |
13470071
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Immunology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
MINATO Nagahiro Kyoto Univ. Grad. Sch. Biostudies Dept. Immunol. Cell Biol. Professor, 生命科学研究科, 教授 (40137716)
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| 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)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| 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)
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| Keywords | PD-1 / PD-L1 / Negative receptors / Autojmmune diseases / Autoantibody / Antoantigen / Dilated cardiomyopathy |
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| 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.
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Report
(3 results)
Research Products
(16 results)
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[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)
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[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)
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[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)
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