SURVIVAL OF ACCOMMODATED CARDIAC XENOGRAFTS UPON RETRANSPLANTATION INTO CYCLOSPORINE-TREATED RECIPIENTS

Background. Accommodation designates the survival of vascularized graf ts in the presence of circulating antigraft antibodies and complement. In the hamster-to-rat model, accommodation is associated with an ongo ing T helper (Th)2 cytokine response and the expression of ''protectiv e genes'' by the graft endothelial cells and smooth muscle cells. In t his report, we tested whether accommodated xenografts would be protect ed from rejection upon retransplantation into second recipients treate d with cyclosporine (CsA), a treatment that does not prolong survival of a fresh hamster heart. Methods. Long-term survival of hamster-to-ra t cardiac xenografts was achieved using either CsA plus cobra venom fa ctor (CVF) or CsA plus rapamycin, Xenografts that survived long term i n their first recipients were retransplanted into second recipients tr eated with CsA. Results. Long-term xenograft survival in CsA/CVF-treat ed recipients was associated with an ongoing Th2 response, expression of protective genes, and deposition of elicited xenoreactive antibodie s and complement on the graft endothelium. In CsA/rapamycin-treated re cipients, long-term xenograft survival occurred in the presence of bas al levels of antigraft antibodies and was not associated with a Th2 cy tokine response or the expression of protective genes. Xenografts from CsA/CVF-treated rats survived significantly longer upon retransplanta tion into second recipients treated with CsA (77.3% >10 days) as compa red with xenografts from CsA/rapamycin-treated rats (4-11 days) or nai ve hearts (3-4 days). Moreover, 30-35% of xenografts from CsA/CVF rats survived long term and accommodated in the second recipient. Conclusi ons. Accommodated xenografts can have significantly prolonged acceptan ce when retransplanted into second recipients treated with CsA alone; in contrast, naive hearts or hearts that survived long term in first r ecipients, but did not accommodate, did not survive long term in the s econd recipients. We suggest that prolonged survival off accommodated xenografts is due to the expression of the protective genes A20, bcP-2 bcl-x(L), and heme oxygenase-1 in the xenograft endothelium and possi bly smooth muscle cells.