RAPAMYCIN INHIBITS TRANSPLANT VASCULOPATHY IN LONG-SURVIVING RAT-HEART ALLOGRAFTS

We have examined the effects of rapamycin (RPM) on transplant vasculop athy in long-surviving F344 rat heart allografts transplanted heteroto pically into Lewis recipients, RPM was administered intraperitoneally for the first 14 days in groups 1 and 2 (0.5 and 2 mg/kg/day), and dai ly throughout the follow-up period in groups 3 (0.5 mg/kg/day) and 4 ( 5 mg/kg for 14 days, followed by a maintenance dose of 2.5 mg/kg/day). Treatment with low dose cyclosporine (CsA; 1.5 mg/kg/day) in combinat ion with RPM (0.5 mg/kg/day for 14 days) (group 5) and immunosuppressi on with CsA only (5 mg/kg for 14 days, followed by 1.5 mg/kg/day) (gro up 6) were also examined, F344 isograft recipients treated with RPM (0 .5 mg/kg/day for 14 days) (group 7), those that were untreated (group 8), and hearts in naive F344 animals (group 9) served as controls. Gra fts of group 1 were removed at 50, 75, 100, 150, and 200 days and infi ltrating cell populations and surface molecules were compared with tho se of the other groups at 100 days. All allografts in treated hosts fu nctioned >100 days; in contrast, grafts in untreated recipients were r ejected acutely by 8+/-1 days (MST +/- SD), The incidence of transplan t vasculopathy in group 1 increased progressively (MST +/- SD = 10+/-2 %, 59+/-7%, 85+/-15%, and 80+/-12% at 50, 100, 150, and 200 days, resp ectively), as manifested by myointimal proliferation with dense mononu clear infiltration (predominantly ED1(+) macrophages), Numbers of MHC class II+ infiltrating cells were prominent, as was expression of adhe sion molecules and cytokines, The incidence of graft disease and exten t of cellular infiltration at 100 days was significantly lower in anim als receiving increased maintenance doses of RPM (for groups 2, 3, and 4: 25+/-15%, 22+/-11%, and 10+/-3%, respectively; P<0.005), CsA treat ment either in combination with RPM or alone (groups 5 and 6) failed t o improve transplant vasculopathy, but reduced mononuclear cell infilt ration, Isografts (groups 7 and 8) and naive hearts (group 9) develope d no structural abnormalities throughout the follow-up period, regardl ess of RPM treatment. We conclude that the extent of transplant vascul opathy can be reduced markedly in this rat cardiac transplant model wi th maintenance RPM, Addition of CsA modifies the morphological picture but does not improve myointimal proliferation.