Inhibition of Ischemia/Reperfusion Injury with the Na+/H+ Exchange Inhibitor Cariporide (Hoe642) Modulates Immunogenicity of Cardiac Allografts and Improves Graft Survival

Abstract

292 Ischemia/reperfusion injury has been suggested to be a major risk factor for the development of chronic allograft dysfunction after solid organ transplantation. Cariporide (Hoe 642), a selective Na+/H+ exchange subtype 1 inhibitor, has been shown to reduce tissue injury following cardiac ischemia in various models of experimental heart disease. The purpose of our study was to assess the effect of cariporide on acute cardiac allograft rejection. Lewis (LEW) rats were challenged with Wistar-Furth (WF) cardiac allografts. In unmodified LEW recipients, WF cardiac allografts survived 6.0±0.5 (n=9) days in group 1. In group 2 cariporide was given orally 7 days preoperatively to donor and recipient animals with standard rat chow. Cardioplegic solution contained 10−6 mol/l cariporide. Recipients received cariporide 7 days postoperatively (30mg/kg body weight, 3x per day, s.c.) and orally by rat chow until graft rejection. Cariporide treatment prolonged cardiac allograft survival to 9.9±1.4 days (n=8, p<0.0001, logrank test). There was no significant difference in ischemic time between group 1 and 2 (20.4±2.9 min, n=20 vs. 20.5±.3.1 min, n=24). Analysis of intragraft events on day 3 and 7 after engraftment revealed a marked reduction of graft infiltrating cells (H&E) in cariporide treated animals. The expression of the adhesion molecule ICAM-1, which has been associated with ischemic injury, was clearly up-regulated in the early phase after transplantation (day 3) only in untreated recipients (immunofluorescence). At the time point of transplant rejection grafts of untreated recipients demonstrated dense infiltration with ED1 positive macrophages and monocytes, α/β positive T cells (R73) and MHC II molecules bearing cells, whereas functioning grafts from Cariporide treated recipients displayed a significantly diminished degree of infiltration (p<0.0001, Wilcoxon-Mann-Whitney test). Cariporide protects cardiac allografts from ischemia/reperfusion injury, prolongs cardiac allograft survival and prevents graft infiltration by mononuclear cells. Therefore, selective inhibition of Na+/H+ exchanger subtype 1 with cariporide can ameliorate ischemia/reperfusion injury and may help to improve long term cardiac allograft survival.