The immunopharmacology of immunosuppression by 15-deoxyspergualin

We have used two murine bioassays, a nonprimarily vascularized heart transplant model and a host-versus-graft (HvG) popliteal lymph node (PLN) hyperplasia assay, to study the novel immunosuppressant, 15-deoxyspergualin (DSG). Using these methods, we investigated DSG's immunosuppressive potency, efficacy, and mechanisms of action. Dose-response studies showed that prolongation of heart allograft survival by DSG was dose dependent with an ED50 ±SD of 1.45±0.39 mg/ kg/day and that DSG was nearly seven times more potent than cyclosporine. Low maintenance doses of 0.25 or 1.0 mg/kg/day of DSG that followed an initial 14-day course of 5.0 mg/kg/day DSG enabled heart allografts to survive for more than 200 days without recipient weight loss or other signs of overt toxicity. When used as treatment for ongoing acute rejection, DSG prolonged graft survival. Although a 30-day course of 5.0 mg/kg/ day of DSG caused significant but reversible body-weight loss, no overt, gross, or histopathologic evidence of significant tissue toxicity was observed in mice treated with 5.0 mg/kg/day DSG for 13 consecutive days. Frequent, intermittent administration of DSG was more immunosuppressive than less frequently administered high doses of DSG, but continuous infusion did not augment drug efficacy or reduce its toxicity. Isobologram analysis of graft survival in recipients treated with both DSG and CsA showed that this drug combi, nation produced synergistic immunosuppression. In contrast to DSG’s efficacy when administered posttransplant, the survival of grafts in recipients that were treated with DSG for 30 days posttransplant was only minimally prolonged. When recipients were sensitized by primary grafts, administration of DSG only during the period of sensitization or only immediately after implantation of secondary grafts failed to prevent accelerated rejection. If, however, graft recipients were treated with DSG both before and after implantation of secondary grafts, accelerated graft rejection was prevented. DSG induced partial alloantigen-specific unresponsiveness, since in DSG-treated C3H recipients of primary BALB/c grafts, secondary BALB/c grafts survived longer than third-party C57BL/6 secondary grafts. A dose of DSG that prolonged graft survival maximally did not suppress the in vivo lymphoproliferative response to alloantigen in the PLN assay. In contrast, doses of CsA that prolonged graft survival minimally suppressed the HVG response significantly. Thus, these studies showed that DSG was a more potent and effective immunosuppressant than CsA, and that DSG treatment prolonged graft survival substantially without apparent toxicity. Furthermore, unlike CsA, a dose of DSG that prolonged heart allograft survival did not suppress alloantigen-stimulated lymphoproliferation in vivo. These results showed that DSG suppressed the immune response by mechanisms of action that differed from other antirejection drugs.