Sirolimus (rapamycin) halts and reverses progression of allograft vasculardisease in non-human primates

Background, Current immunosuppressive protocols fail to prevent chronic rej ection often manifested as graft vascular disease (GVD) in solid organ tran splant recipients, Several new immunosuppressants including sirolimus, a du al function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantifie d by intravascular ultrasound (IVUS), Methods, Twelve cynomolgus monkeys underwent aortic transplantation from bl ood group compatible but mixed lymphocyte reaction-mismatched donors. To al low the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105, Results, Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkey s (P < 0.001, general linear model). On day 105, the intimal area+/-SEM was 3.7+/-1.0 and 6.4+/-0.5 mm(2), respectively (P < 0.05, t test). The magnit ude of allograft intimal area on day 105 correlated inversely with sirolimu s trough levels (R-2=0.67, P < 0.05). Regression of the intimal area was se en in four of six sirolimustreated monkeys, which was significantly differe nt from the untreated monkeys (P < 0.05), Conclusions. Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisti ng GVD but also was associated with partial regression. Sirolimus trough bl ood levels were correlated with efficacy. Therefore, sirolimus has the pote ntial to control clinical chronic allograft rejection.