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(Circulation. 2003;107:2369.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Sirolimus (Rapamycin) Monotherapy Prevents Graft Vascular Disease in Nonhuman Primate Recipients of Orthotopic Aortic Allografts

Camille Dambrin, MD; Jochen Klupp, MD; Tudor Bîrsan, MD; Jorge Luna, MD; Takeshi Suzuki, MD; Tuan Lam, MD; Peter Stähr, MD; Bernard Hausen, MD; Uwe Christians, MD; Peter Fitzgerald, MD; Gerald Berry, MD; Randall Morris, MD

From Transplantation Immunology, Cardiothoracic Surgery (C.D., J.K., T.B., T.L., B.H., R.M.), Cardiovascular Medicine (J.L., T.S., P.S., P.F.), and Pathology (G.B.), Stanford University, Stanford, and Biopharmaceutical Sciences, University of California, San Francisco (U.C.), San Francisco, Calif.

Correspondence to Randall E. Morris, MD, Transplantation and Immunology Research, Novartis Pharma AG, WSJ-386.610, Basel, CH-4002, Switzerland. E-mail rem{at}stanford.edu

Background— Delayed treatment with sirolimus (SRL) halts progression of graft vascular disease (GVD) in nonhuman primate (NHP) aortic allograft recipients. In this study, we investigated whether SRL monotherapy prevents the development of GVD.

Methods and Results— Pairs of 3-cm infrarenal aortic segments were exchanged between mixed lymphocyte reaction–mismatched, blood group–compatible NHPs (n=12). Six NHPs were untreated controls, and 6 were treated orally with SRL starting on the day of transplantation. Follow-up was 105 days. SRL doses were adjusted individually by assessing SRL blood concentrations, immune function, and clinical status. The severity of GVD was determined every 3 weeks by intravascular ultrasound, which quantified intimal area (IA) and intimal volume (IV) for the middle 1-cm graft segments. The mean±SEM SRL plasma levels were 14.5±9 ng/mL. In grafts from treated NHPs, IA and IV values on days 63, 84, and 105 were significantly lower than for controls (P<0.05 to P<0.001). On day 105, in the grafts from SRL-treated NHPs compared with grafts from controls, values (mean±SEM) were IA, 2.9±0.9 versus 5.5±0.7 mm², P<0.001 and IV, 29.6±4.6 versus 55.2±2.8 mm³, P<0.001; IA and IV values for grafts from SRL-treated NHPs did not increase significantly between days 21 and 105.

Conclusions— We show that SRL monotherapy prevented GVD in NHP aortic allograft recipients, suggesting the value of SRL for controlling GVD in clinical transplantation.

Key Words: transplantation • arteriosclerosis • prevention • immunology