THE IMPACT OF ACUTE REJECTION ON THE DEVELOPMENT OF INTIMAL HYPERPLASIA ASSOCIATED WITH CHRONIC REJECTION

The rate aortic model of chronic rejection was used to study the effec t of acute rejection on the development of intimal hyperplasia (IH). T wo model systems were studied. In the first, continuous monotherapy wi th mycophenolate mofetil (MM) (40 mg/d 14 d followed by 30 mg/kg/d) wa s initiated 2 or 4 weeks posttransplant. Digital computer image analys is was used to quantify IH. While the development of IH was delayed, i t was not prevented. In allografts where MM treatment was delayed for 2 wk, a 35.5% reduction in the amount of IH was observed. Delaying dru g treatment for 4 wk resulted in a 42.4% reduction of IH. In contrast, continuous therapy from the time of transplant resulted in a 76.3% re duction in the amount of IH in comparison with untreated allograft con trols. To further define the role of acute rejection in the developmen t of IH, aortic allografts, ACI or (ACIxLewis)F-1 (F-1), were orthotop ically transplanted to Lewis recipients and then retransplanted to don or strain secondary recipients after 2 or 4 wk. Grafts were harvested at 12 weeks posttransplant. When the transplant was performed at 2 wk, intimal hyperplasia was decreased by 55.9% in ACI and by 66.7% in F-1 allografts in comparison to conventional (ACI-->Lewis) allograft cont rols. When retransplantation was delayed until 4 wk, IH was not decrea sed in ACI allografts (105.9%) and was only marginally decreased in F- 1 allografts (26.2%). Syngeneic control F-1 grafts (F-1-->F-1-->F-1) d id not develop significant IH at 12 or 20 wk when retransplantation at 2 wk (10% and 12%, respectively) or when retransplanted at 4 wk and h arvested at 12 wk (18.6%). A common feature of IH is the development o f medial acellularity. Unlike conventional allograft recipients (ACI-- >Lewis; no retransplantation), F-1 retransplanted grafts did not devel op significant medial myocyte dropout. In contrast, delayed MM immunos uppressive therapy or retransplantation of ACI allografts at 4 weeks t o ACI secondary recipients resulted in significant loss of medial myoc ytes. Our results show that acute rejection, which occurs during the f irst 4 wk posttransplant, is sufficient to mediate the development of IH associated with CR. However the lack of a continued allogenic envir onment slows the process.