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.
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)-gamma 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-gamma-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.
Hwang
M W
MW
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Matsumori
A
A
Furukawa
Y
Y
Ono
K
K
Okada
M
M
Iwasaki
A
A
Hara
M
M
Sasayama
S
S
D000818:Animals; D003324:Coronary Artery Disease / Q000517:prevention & control*; D016572:Cyclosporine / Q000627:therapeutic use; D018450:Disease Progression; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011183:Postoperative Complications / Q000517:prevention & control; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D007371:Interferon-gamma; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine