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.
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.


RESULTS
We used a murine heterotopic cardiac transplantation model between fully incompatible strains and administered 500 microg x kg(-1) x 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-gamma and enhanced the expression of transforming growth factor-beta1 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.
Yamaura
Kazuhiro
K
Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
Ito
Ken-ichi
K
Tsukioka
Katsuaki
K
Wada
Yuko
Y
Makiuchi
Akiko
A
Sakaguchi
Masayuki
M
Akashima
Tomohiro
T
Fujimori
Minoru
M
Sawa
Yoshiki
Y
Morishita
Ryuichi
R
Matsumoto
Kunio
K
Nakamura
Toshikazu
T
Suzuki
Jun-ichi
J
Amano
Jun
J
Isobe
Mitsuaki
M
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002908:Chronic Disease; D004341:Drug Evaluation; D020869:Gene Expression Profiling; D006084:Graft Rejection / Q000188:drug therapy*; D016027:Heart Transplantation; D017228:Hepatocyte Growth Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D007165:Immunosuppression Therapy / Q000379:methods; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016038:Skin Transplantation; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous; D014657:Vasculitis / Q000188:drug therapy / Q000517:prevention & control
D002316:Cardiotonic Agents; D007155:Immunologic Factors; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor