Cyclosporin as an adjunct to the induction of specific unresponsiveness

Abstract

The induction of allo-unresponsiveness remains a major goal in clinical organ transplantation. In the interim, the physician must rely upon nonspecific immunosuppressive agents to dampen host responses. Initial drugs displayed relatively poor selectivity for T-lymphocyte responses. Azathioprine acting via a competitive, and cyclophosphamide acting via a noncompetitive, mechanism inhibit nucleic acid replication by all dividing cells. Since their inhibitory effects are more pronounced on bone marrow than on T cells, they rarely achieve effective allograft rejection prophylaxis. Corticosteroids, which interfere with antigen processing and signal reception in a non-specific fashion, have been implicated as a major contributing factor to infectious complications in transplant recipients. Introduction of cyclosporin (CsA) proffers a drug relatively selective for T-cell-dependent immune responses, with little effect on monocyte/macrophage.. polymorphonuclear leukocyte and/or natural killer cell resistance. However, the depression of T-cell-mediated resistance in a nonspecific fashion continues to permit viral and protozoal superinfection. Thus, major goals of current research are to optimize the CsA therapeutic effect, to dampen alloimmunity versus other T-cell functions and to minimize nephrotoxic and hepatotoxic complications, thereby providing a foundation for induction of specific unresponsiveness.