Anti-CD4 monoclonal antibody treatment combined with total lymphoid irradiation and cyclosporin A in hamster-to-rat cardiac transplantation: Analysis of lymphocyte subsets and anti-donor xenoantibodies

Abstract

Combined treatment with total lymphoid irradiation and cyclosporin A results in prolonged graft survival in concordant xenogeneic cardiac transplantation, but reproducible long-term graft acceptance has proved to be difficult. Anti-CD4 monoclonal antibody treatment has been successful in inhibiting heart graft rejection in allogeneic models. Used as monotherapy in a concordant xenogeneic model for pancreatic islet transplantation, prolonged graft survival has been reported; however, no beneficial effect on primarily vascularized heart grafts was noted. The object of this investigation was to combine these treatment strategies with respect to reproducible long-term hamster heart graft survival in rats, to monitor the effect on lymphocyte subpopulations, and to determine possible anti-donor antibody formation correlated to time of rejection. Graft survival after combined preoperative total lymphoid irradiation and postoperative cyclosporin A + anti-CD4 monoclonal antibody treatment was prolonged from 14 to > 100 days (compared to spontaneous graft survival of three to four days), with long-term graft function in four of 19 recipients. Total white blood counts in the postoperative course were characterized by an unproportional increase of Ig+ cells and an incomplete recovery of CD4+ cells. Flow-cytometric analysis of anti-donor antibodies showed low levels of performed antibodies and increasing amounts of strain-, but not donor-specific antibodies, correlated to the time of rejection. Long-term survivors with functioning grafts at the time of sacrifice had an initially moderate antibody increase with subsequent decrease to baseline levels. Our results indicate that total lymphoid irradiation combined with cyclosporin A and anti-CD4 monoclonal antibodies can prolong graft survival significantly in concordant hamster-to-rat cardiac xenotransplantation. Graft rejection seems to be of a delayed antibody-mediated type, where the inhibition of T cell help for antibody formation may play a significant role.