Cyclosporin (CsA) and FK-506 are structurally distinct fungal metabolites, which exert powerful inhibitory effects on CD4+ T (helper) cell activation and on the secretion of interleukin-2 (IL-2) and other cytokines, including various cell growth factors and interferon-gamma. Both drugs also inhibit IL-2 receptor expression on T cells. Consequently, when administered from the time of transplant surgery, both CsA and FK-506 inhibit the generation and proliferation of cytotoxic T cells which would otherwise mediate allograft rejection; T-cell dependent antibody responses are also inhibited by both drugs. CsA and FK-506 however, differ markedly in immunosuppressive potency. FK-506 is at least 100 times as potent as CsA in inhibiting human mixed lymphocyte reactions in vitro, whilst the ID50 of FK-506 for inhibition of allograft survival in animals is approximately one tenth that of CsA. FK-506 and CsA, both of which are highly lipophilic molecules, bind to distinct cytosolic proteins, each of which is a peptidyl-prolyl isomerase and the activities of which may play critical roles in signal transduction within activated T cells. The precise molecular mechanism by which these drugs selectively inhibit cytokine gene expression at a pretranscriptional level is not understood but a transcription activator has been implicated as the target. Compared with CsA, the inhibitory action of FK-506 appears more difficult to reverse, e.g., in response to pre-formed IL-2. Both drugs are however, ineffective in inhibiting directly the cytotoxic activity of cytotoxic T cells. In the rat, short courses of CsA or FK-506 can induce donor-specific tolerance to graft alloantigens; with CsA, and perhaps also with FK-506, this condition is maintained by T suppressor cells. Remarkably in rats, FK-506 has the capacity, not shared with CsA, to reverse allograft rejection. This property has also been exhibited, at low dosage, in the first clinical trial of FK-506 in liver transplantation. The macrolide rapamycin (RAPA) is the closet known structural analogue of FK-506. Like FK-506, it is a very potent immunosuppressant and prolongs allograft survival in rodents, dogs and pigs. Unlike CsA and FK-506 however, it does not inhibit IL-2 production, but inhibits the responses of T cells to this and other cytokines. Recent data indicate that RAPA and FK-506 are reciprocal antagonists. The potential of RAPA in clinical organ transplantation has not yet been evaluated.
