The immunosuppressive drugs cyclosporin A (CsA) and FW06 have proven to be extremely powerful therapeutic agents both in the prevention of allograft rejection following solid organ engraftment and in the prophylatic treatment of graft-versushost disease after bone marrow tran~ plantation. l-~ The immunosuppressive properties of CsA and FK. 506 can largely be ascribed to their potent inhibition of the T cell activation dependent transcription of the T cell growth factor interleukin 2 and other immunologically important T lymphocyte derived lymphokines. M In normal T lymphocytes, physiological triggering of the T cell antigen receptor results in the generation of a number of distinct intracellular biochemical signals (eg, elevated intracellular calcium, activation of protein kinase C, and tyrosine phosphorylation), which together act to initiate the orderly expression of specific T cell genes resulting in T cell activation, cellular proliferation, and ultimately acquisition of immune functi~ n.~?~ Although structurally unrelated, both CsA and FK506 inhibit this complex sequence of events at a similar step. In this regard, CsA and FK506 do not inhibit the initial generation of biochemical second messengers, but rather, act at a subsequent step in the signaling cascade to specifically interfere with a Caz+-sensitive T cell signal transduction thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A) involved in lymphokine gene expres~ ion.~ J* ls

CsA and FK506 appear to act via interaction with their cognate intracellular receptors,'" Ix cyclophilin and FKBP, respectively (reviewed in Reference 19). Despite the lack of any significant homology between these two receptor families, both possess peptidyl prolyl-cis-trans isomerase activity, an enzymatic activity involved in the catalysis of the cis-trans isomerization of proline residues in polypeptide The observation that CsA and FW06 specifically inhibit the isomerase activity of their respective re~ eptor I~-*~ led initially to the notion that isomerases were directly involved in T cell activation. Arguing against this simple model is the observation that certain nonimmunosuppressive analogues of FK506 can bind to FKBP fully inhibiting its isomerase activity and, moreover, can antagonize the inhibitory effects of FK. 506.16, 17, 1y These and other findings have led to the proposal