The immunosuppressive macrolides FK-506 and rapamycin.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Thomson
A W
AW
Department of Pathology, University of Aberdeen, Medical School, Foresterhill, U.K.
D000818:Animals; D006085:Graft Survival / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016377:Organ Transplantation; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus; D016559:Tacrolimus