Published Online
on September 13, 2004

A more recent version of this article appeared on September 21, 2004

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Submitted on June 3, 2004
Revised on July 12, 2004
Accepted on July 26, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: kenito{at}hsp.md.shinshu-u.ac.jp.

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-1 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

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