A POTENTIAL SYNERGISTIC EFFECT OF DONOR ANTIGENIC EXTRACTS AND CYCLOSPORINE ON THE PROLONGATION OF RAT RENAL ALLOGRAFTS

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Abstract
Administration of 5 daily doses of 15 mg/kg cyclosporine on the day before, the day of and 3 days after, renal transplantation prolonged the survival of Buffalo (BUF) renal allografts in Wistar-Furth recipients from a mean survival time (MST)of 7.9 .+-. 0.74 to 25.5 .+-. 1.2 days. The immunologic effects of this brief cyclosporine course were assessed using spleen cells harvested 5 days after tranplantation. Cyclosporine abrogated both the direct lymphocyte-mediated cytolysis of donor 51Cr-labeled BUF targets, and the early, 3-day enhanced proliferation, and it stimulated lympholysis of labeled donor cells markedly after restimulation in vitro with BUF lymphocytes. Cyclosporine apparently disrupts the maturation of both proliferative and cytotoxic precursors of the alloimmune response. A potentially synergistic effect of soluble donor antigen with cyclosporine was postulated, because 3 M KCl extracts are capable of directly stimulating both suppressor T cells and helper T cells. Because the activity of T helper cells appeared in these experiments to be dampened by cyclosporine, antigen stimulation of suppressor cells could lead to unresponsiveness. On the day prior to transplanation, 5 mg of a 3 M KCl extract of BUF spleen (Ag) was administered i.v. in addition to the cyclosporine regimen. Although there was no difference in the overall survival of grafts in the Ag-cyclosporine group and the cyclosporine only group, the Ag-cyclosporine regimen did prolong graft survival significantly in the subset of animals with grafts functioning > 35 days (Ag-cyclosporine MST = 109.5, cyclosporine alone MST = 54 days). The selective properties of cyclosporine and of soluble antigen treatments may be used to achieve unresponsiveness without the hazards of continued administration of immunosuppressive agents.