This Article Full Text Full Text (PDF) All Versions of this Article: 110/12/1650    most recent 01.CIR.0000143052.45956.71v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamaura, K. Articles by Isobe, M. Search for Related Content PubMed PubMed Citation Articles by Yamaura, K. Articles by Isobe, M. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Heart Transplantation Related Collections Other myocardial biology Animal models of human disease Apoptosis Other arteriosclerosis Growth factors/cytokines CV surgery: transplantation, ventricular assistance, cardiomyopathy

(Circulation. 2004;110:1650-1657.)
© 2004 American Heart Association, Inc.

Transplantation

Suppression of Acute and Chronic Rejection by Hepatocyte Growth Factor in a Murine Model of Cardiac Transplantation

Induction of Tolerance and Prevention of Cardiac Allograft Vasculopathy

Kazuhiro Yamaura, MD; Ken-ichi Ito, MD, PhD; Katsuaki Tsukioka, MD, PhD; Yuko Wada, MD, PhD; Akiko Makiuchi, MD; Masayuki Sakaguchi, MD; Tomohiro Akashima, PhD; Minoru Fujimori, MD, PhD; Yoshiki Sawa, MD, PhD; Ryuichi Morishita, MD, PhD; Kunio Matsumoto, PhD; Toshikazu Nakamura, PhD; Jun-ichi Suzuki, MD, PhD; Jun Amano, MD, PhD; Mitsuaki Isobe, MD, PhD

From the Department of Surgery (K.Y., K.-i.I., K.T., Y.W., A.M., M.S., T.A., M.F., J.A.), Shinshu University School of Medicine, Matsumoto; the Department of Surgery (Y.S.), the Division of Clinical Gene Therapy (R.M.), and the Division of Molecular Regenerative Medicine (K.M., T.N.), Osaka University Graduate School of Medicine, Osaka; and the Department of Cardiovascular Medicine (J.-i.S., M.I.), Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan.

Correspondence to Ken-ichi Ito, MD, PhD, Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail kenito{at}hsp.md.shinshu-u.ac.jp

Received June 3, 2004; revision received July 12, 2004; accepted July 26, 2004.

Background— Although treatment with immunosuppressive agents has contributed to overcoming acute rejection and improving the midterm survival of transplanted hearts, cardiac allograft vasculopathy (CAV) has remained the main cause of primary graft failure. Recent approaches have shown that hepatocyte growth factor (HGF) exhibits cardiotrophic functions. We therefore addressed whether HGF would regulate acute and chronic rejection in cardiac transplantation.

Methods and Results— We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 µg · kg^–1 · d^–1 HGF during the initial 14 days after transplantation. The HGF-treated allografts showed significantly prolonged survival (42.3±4.1 days, P<0.001) compared with the controls (11.1±0.6 days), with tolerance induction in 47.4%. Histopathologically, the number of infiltrating cells was significantly decreased and myocardial necrosis was less prominent with a reduction of apoptosis in the allografts by HGF treatment during acute rejection. In the long-term surviving allografts, HGF significantly inhibited the development of CAV and interstitial fibrosis. With respect to intragraft cytokine mRNA expression, HGF treatment reduced the early expression of interferon- and enhanced the expression of transforming growth factor-ß1 during the acute phase and of interleukin-10 continuously through the acute phase to the chronic phase.

Conclusions— Our findings demonstrate that HGF can prolong the survival of allografts by its cardioprotective and immunomodulative potencies. Thus, HGF administration may constitute a new therapeutic approach to preventing cardiac graft failure that has not been overcome by conventional immunosuppressive agents.

Key Words: pathology • growth substances • immune system • rejection • transplantation

This article has been cited by other articles:

				K. D. McCall-Culbreath, Z. Li, and M. M. Zutter Crosstalk between the {alpha}2{beta}1 integrin and c-met/HGF-R regulates innate immunity Blood, April 1, 2008; 111(7): 3562 - 3570. [Abstract] [Full Text] [PDF]

				A. Naji, S. Le Rond, A. Durrbach, I. Krawice-Radanne, C. Creput, M. Daouya, J. Caumartin, J. LeMaoult, E. D. Carosella, and N. Rouas-Freiss CD3+CD4low and CD3+CD8low are induced by HLA-G: novel human peripheral blood suppressor T-cell subsets involved in transplant acceptance Blood, December 1, 2007; 110(12): 3936 - 3948. [Abstract] [Full Text] [PDF]

				K. Okunishi, M. Dohi, K. Fujio, K. Nakagome, Y. Tabata, T. Okasora, M. Seki, M. Shibuya, M. Imamura, H. Harada, et al. Hepatocyte Growth Factor Significantly Suppresses Collagen-Induced Arthritis in Mice J. Immunol., October 15, 2007; 179(8): 5504 - 5513. [Abstract] [Full Text] [PDF]

				S. Rutella, G. Bonanno, A. Procoli, A. Mariotti, D. G. de Ritis, A. Curti, S. Danese, G. Pessina, S. Pandolfi, F. Natoni, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features Blood, July 1, 2006; 108(1): 218 - 227. [Abstract] [Full Text] [PDF]

				D. Tormo, A. Ferrer, P. Bosch, E. Gaffal, E. Basner-Tschakarjan, J. Wenzel, and T. Tuting Therapeutic Efficacy of Antigen-Specific Vaccination and Toll-Like Receptor Stimulation against Established Transplanted and Autochthonous Melanoma in Mice. Cancer Res., May 15, 2006; 66(10): 5427 - 5435. [Abstract] [Full Text] [PDF]

				V. Nilakantan, X. Zhou, G. Hilton, Y. Shi, J. E. Baker, A. K. Khanna, and G. M. Pieper Antagonizing reactive oxygen by treatment with a manganese (III) metalloporphyrin-based superoxide dismutase mimetic in cardiac transplants J. Thorac. Cardiovasc. Surg., April 1, 2006; 131(4): 898 - 906. [Abstract] [Full Text] [PDF]

				K. Okunishi, M. Dohi, K. Nakagome, R. Tanaka, S. Mizuno, K. Matsumoto, J.-i. Miyazaki, T. Nakamura, and K. Yamamoto A Novel Role of Hepatocyte Growth Factor as an Immune Regulator through Suppressing Dendritic Cell Function J. Immunol., October 1, 2005; 175(7): 4745 - 4753. [Abstract] [Full Text] [PDF]

				H. Futamatsu, J.-i. Suzuki, S. Mizuno, N. Koga, S. Adachi, H. Kosuge, Y. Maejima, K. Hirao, T. Nakamura, and M. Isobe Hepatocyte Growth Factor Ameliorates the Progression of Experimental Autoimmune Myocarditis: A Potential Role for Induction of T Helper 2 Cytokines Circ. Res., April 29, 2005; 96(8): 823 - 830. [Abstract] [Full Text] [PDF]