Die Kombinationen von Donor-spezifischen Transfusionen mit Cyclosporin A oder Rapamycin haben unterschiedliche Effekte auf die Toleranzinduktion für kardiale Allotransplantate und die Entstehung kardialer Allograftvaskulopathie im Miniaturschweinmodell

Abstract

Purpose: To evaluate the effect of pretransplant donor-specific transfusion combined with cyclosporine A and rapamycin on tolerance induction to cardiac allografts in a clinically relevant large-animal model. Methods: Heterotopic cardiac transplants were performed across a major histocompatibility complex (MHC) class I barrier in MHC-inbred miniature swine. Experimental animals were treated with two donor-specific transfusions (DSTs), each containing 1.4 × 108 viable peripheral blood mononuclear cells, 14 and 7 days prior to heart transplantation. All animals received a 12-day course of cyclosporine (CyA) (trough level 300–800 ng/ml) or rapamycin (RPM) (trough level 10–20 ng/ml) starting on post-operative day (POD) 0. Control groups received CyA or RPM alone, DST alone or no treatment. Cell mediated lympholysis (CML) assays were performed at regular intervals. T cell priming and activation induced cell death (AICD) were assessed by carboxyfluoroscein succinimidyl ester (CFSE) proliferation assays and Annexin V staining. Results: Untreated (n = 2) and DST-only (n = 2) treated control animals rejected between POD 6 and 8. Animals treated with CyA (n = 3) or RPM (n = 3) alone exhibited graft survival to 53, 52 and 59 days or 41, 50 and 53 days, respectively. In contrast, DST-pretreatment combined with CyA (n = 3) led to stable graft function for > 200 days in all animals. Grafts in recipients treated with pretransplant DST and RPM (n = 4) survived 52, 45, 100 and > 200 days. Like the controls, long-term acceptors in the DST+CyA group and DST+RPM group mostly maintained peripheral CML response against donor and third party antigen. Following DSTs, the donor-specific proliferative response of CD8+ recipient T cells was significantly increased on CFSE assay (p = 0.011), and a significant number of recipient CD8+ T cells underwent apoptosis (10.1% on POD 0 versus 5.2% on POD -14; p = 0.04).