A potential synergistic effect of donor antigenic extracts and cyclosporine on the prolongation of rat renal allografts.
Administration of five daily doses of 15 mg/kg Cyclosporine on the day before, the day of, and three 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 five days after transplantation. Cyclosporine abrogated both the direct lymphocyte-mediated cytolysis of donor 51Cr-labelled BUF targets, and the early, three-day enhanced proliferation, and it stimulated lympholysis of labelled donor cells markedly after restimulation in vitro with BUF lymphocytes. Therefore, cyclosporine 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 transplantation, 5 mg of a 3 M KCl extract of BUF spleen (Ag) was administered intravenously 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 more than 35 days (Ag-cyclosporine MST = 109.5, cyclosporine alone MST = 54 days). Therefore, it may be possible to exploit the selective properties of cyclosporine and of soluble antigen treatments to achieve unresponsiveness without the hazards of continued administration of immunosuppressive agents.
D000818:Animals; D003524:Cyclosporins / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D007111:Immunity, Cellular / Q000187:drug effects; D007165:Immunosuppression Therapy; D007519:Isoantigens / Q000276:immunology*; D016030:Kidney Transplantation; D008213:Lymphocyte Activation; D051381:Rats
D003524:Cyclosporins; D007519:Isoantigens