Rapamycin reverses chronic graft vascular disease in a novel cardiac allograft model

Background-Chronic graft vascular disease (CGVD) in cardiac allografts has been defined as a slowly evolving vasculopathy unresponsive to conventional immunosuppression. We compared 4 rodent models of CGVD to evaluate the rep roducibility of CGVD in heart allografts. Rapamycin (Rapa) and cyclosporine (CSA) were then used to treat CGVD, Methods and Results-Hearts were harvested and placed heterotopically into a llogenic recipients. CGVD scores of PVG allografts from ACI recipients trea ted with CSA on days 1 through 10 were significantly elevated on day 90 (n = 16) compared with other models (immunosuppression used): (1) Lewis to F34 4 recipients (CSA), (2) Brown Norway to Lewis (FK506),and (3) DA to Wistar- Firth (methylprednisolone, azathioprine, CSA). Although delayed (day 60 to 90) CSA treatment had no effect (n = 6), delayed Rapa (3 mg.kg(-1).d(-1) IP ) reversed CGVD in PVG grafts (0.22 +/- 0.19 on day 90, n = 6). ACI isograf ts showed no evidence of CGVD (n = 6) at day 90. Immunohistochemistry of PV G grafts revealed perivascular infiltrates consisting of CD4(+) T cells and limited numbers of macrophages persisting up to day 90. Flow cytometry dem onstrated increased levels of anti-donor antibody at day 90, which was sign ificantly inhibited by Rapa treatment. Conclusions-PVG grafts developed a significant increase in CGVD without evi dence of ongoing myocardial rejection. This CGVD appeared to be mediated by both cellular and humoral mechanisms, given CD4(+) perivascular infiltrate s and increased levels of anti-donor antibody. The anti-CGVD effectiveness of Rapa during a period in which there was little myocardial cellular infil trate supports a novel mechanism of effect such as smooth muscle or B-cell inhibition.