INDUCTION OF DONOR-SPECIFIC UNRESPONSIVENESS TO CARDIAC ALLOGRAFTS IN RATS BY PRETRANSPLANT ANTI-CD4 MONOCLONAL ANTIBODY THERAPY

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Abstract
In the present report a monoclonal antibody designated OX-38 directed against the rat CD4 molecule was tested for its ability to prolong the survival of heterotopic vascularized rat hearts allografts transplanted across major histocompatibility barriers. Fluorescence-activated cell-sorter analysis showed that administration of OX-38 selectively depleted 80-95% of CD4+ cells from peripheral blood of treated rats. The immunosuppressive effects of OX-38 in vivo were verified by suppression of an antibody response against OX-38 itself as a heterologous protein immunogen. Recipient rats received OX-38 antibody as a single agent given in pretransplant regimens. Nine of 12 treated rats have maintained heterotopic abdominal heart allografts for >175 days. Controls rats that did not receive antibody therapy rejected their grafts within 14 days. Rats that maintained heart allografts for >100 days accepted second donor strain hearts but rejected third-part heart grafts transplanted into the femoral sapace. Anti-CD4-induced allograft unresponsivesness persisted for at least 90 days following surgical removal of donor tissue and retransplantation of a second donor-matched heart. These results indicated that transient, pretransplant therapy with monoclonal antibodies directed against the CD4+ lymphocyte induced specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosupression.