Improved experimental cardiac xenograft survival with cyclophosphamide and intrathymic donor cells

Abstract

Abstract: Tolerance to cardiac allografts can be induced by pretreatment of the recipient with antilymphocyte serum (ALS) and intrathymic donor cells. Our previous efforts to extend this observation to experimental cardiac xenografts in a usually concordant species combination led to antibody and complement mediated hyperacute rejection. Hyperacute rejection can be abrogated by the use of cobra venom factor but this agent even in combination with intrathymic pretreatment is not successful in prolonging xenograft survival in this model. In contrast to the immune response to allografts, which is predominately mediated by T cells, a B cell antibody mediated response plays an important role in xenotransplantation. Cyclophosphamide is active against dividing B cells. In the present experiments in a concordant hamster to rat cardiac xenograft model, we used the combination pretreatment of cyclophosphamide (20 mg/kg IV) injected on days ‐19, ‐16, ‐13, and‐10 prior to heart transplantation, ALS (1 ml intraperitoneally), and hamster spleen cells (25 × 106 intrathymically) given on day ‐18, 1 day after the first dose of cyclophosphamide. Grafted hearts were assessed by daily palpation of the graft pulse through the abdominal wall of the recipient. In untreated control recipients, graft survival was uniformly 3 days. Significant prolongation of graft survival was seen in pretreated animals whose grafts survived 4, 5, 5, 6, and 6 (mean 5.2) days (P<0.01). These studies show that an anti B cell regimen, when coupled with intrathymic pretreatment, results in prolongation of experimental cardiac xenograft survival. However, in contrast to allotransplantation, permanent tolerance cannot be achieved by this pretreatment protocol.