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(Circulation. 1999;100:1322-1329.)
© 1999 American Heart Association, Inc.

Basic Science Reports

FTY720, a New Immunosuppressant, Promotes Long-Term Graft Survival and Inhibits the Progression of Graft Coronary Artery Disease in a Murine Model of Cardiac Transplantation

Myung-Woo Hwang, MD; Akira Matsumori, MD, PhD; Yutaka Furukawa, MD, PhD; Koh Ono, MD, PhD; Masaharu Okada, MD; Atsushi Iwasaki, MD; Masatake Hara, MD; Shigetake Sasayama, MD, PhD

From the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Correspondence to Akira Matsumori, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-8397, Japan. E-mail amat{at}kuhp.kyoto-u.ac.jp

Background—Effective immunosuppression is a critical determinant of organ and patient survival in cardiac transplantation. The present study was designed to determine the potency of FTY720, a new synthesized immunosuppressant, and examine its clinical potential as an immunosuppressant.

Methods and Results—Hearts of DBA/2 mice were transplanted heterotopically in C57BL/6 mice. Recipients were treated with oral FTY720 in doses of 0.3, 1, 3, or 10 mg · kg^-1 · d^-1 or with 40 mg · kg^-1 · d^-1 of cyclosporin A (CsA) as a comparative treatment. The median graft survival time (MST) was significantly prolonged by treatment with FTY720 10 mg · kg^-1 · d^-1. MST was not prolonged by FTY720 1 mg · kg^-1 · d^-1 or CsA. However, FTY720 1 mg · kg^-1 · d^-1 combined with CsA 40 mg · kg^-1 · d^-1 resulted in a significant prolongation of MST. Histopathological studies performed 5 days after transplantation demonstrated remarkable suppression of inflammatory response by treatment with FTY720 10 mg · kg^-1 · d^-1. Interleukin (IL)-2 and interferon (IFN)- production was not suppressed; however, cytotoxic T lymphocyte activity was strongly suppressed in vitro. In addition, IL-2–stimulated T-cell proliferation and class I and class II MHC antigen expression on IFN-–stimulated macrophages were strongly inhibited by FTY720. Histopathological studies 60 days after transplantation (DBA/2-B10.D2) demonstrated a beneficial effect on graft atherosclerosis.

Conclusions—FTY720 promoted long-term cardiac graft survival and strongly inhibited the progression of graft atherosclerosis. These observations suggest that FTY720 has a promising clinical potential in cardiac transplantation.

Key Words: FTY720 • immunology • transplantation • rejection • grafting • hormones

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