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Immunomodulators: Immunophilins
 | | | High rates of post-transplantation survival and organ retention have been attributed, in large part, to the availability of immunosuppressive drugs such as Cyclosporin A (CsA) and FK506. These drugs allow the patient to overcome the normal immune-based rejection of a foreign organ. They suppress the immune response by blocking the activation of T lymphocytes. The term “immunophilins” refers to a number of intracellular receptor proteins that bind with high affinity to immunosuppressant agents such as CsA, FK506 and Rapamycin. These proteins, which have distinct specificities for CsA and FK506/Rapamycin, are known as cyclophilins and FKBPs (FK506/Rapamycin binding proteins), respectively. These receptor proteins were shown to possess peptidylproline cis-trans isomerase (PPIase or rotamase) activity, which is inhibited upon binding to their cognate ligand. This led to a belief that immunosuppressive activity of these drugs was due to the loss of rotamase activity. However, some drug analogs that inhibit rotamase activity fail to suppress the immune response. Now it is generally accepted that CsA/FK506, and Rapamycin appear to cause immunosuppression through totally different mechanisms. More recently, it has been shown that PPIase activity of cyclophilins contributes to protein folding and acts as a chaperone. CsA and FK506 inhibit T cell proliferation at an early stage by preventing transcription of IL-2 and other early growth response genes, whereas Rapamycin blocks signaling from the IL-2 receptor after IL-2 synthesis. Complexes of CsA/cyclophilin and FK506/FKBP12 bind to calcineurin, a Ca2+-dependent phosphatase, and inhibit its activity. This prevents the translocation of the cytoplasmic component of the transcription factor, which is the nuclear-factor of activated T-cells (NF-AT) required for IL-2 gene expression and Tcell activation. Although Rapamycin binds to FKBP12, the complex does not interact with calcineurin. Instead, the Rapamycin-FKBP12 complex binds to a protein designated Rapamycin and FKBP12 target-1 (RAFT1) in rats or FKBP-Rapamycin-associated protein (FRAP) in humans. Since RAFT1 displays homology to several phosphatidylinositol (PI) kinases, it has been suggested that RAFT1 may also be a PI kinase and that Rapamycin exerts its immunosuppressant effect by inhibiting this PI kinase activity.
Clinical studies with CsA have also demonstrated the potential use of immunosuppressants in the treatment of autoimmune diseases such as rheumatoid arthritis, asthma, psoriasis, and Crohn’s disease. Both CsA and FK506 exhibit major toxic side effects, in particular, nephrotoxicity and neurotoxicity, which limit their use. Since it has been demonstrated that toxicities of these compounds are mechanism-related, major efforts are being directed towards more selective, alternate immunosuppressive strategies. Several non-immunophilin-based immunosuppressants are currently undergoing clinical trials to test their efficacy. Several immunosuppressants are also valuable tools for elucidating intracellular signaling systems. They have been linked to modulation of neurotransmitter release as well as mediation of nerve regeneration and prevention of the neurotoxic effects of NMDA. | | | References:
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