Immunosuppressive drug action

Immunophillins are abundant proteins that catalyze the cis-trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins are not essential proteins, are the intracellular binding proteins of several immunosuppressive drugs. Cyclosporin A exerts its action after binding to cyclophilin. Tacrolimus and sirolimus predominantly bind to the protein FKBP-12 (FK binding protein-12). 

Immunosuppressive drugs comprise a large spectrum of substances with different mechanisms of action where T-lymphocytes represent a major target [1, 2]. In general, immunosuppressants can be divided into those that... 

Morris RE. (1995) Mechanisms of action of new immunosuppressive drugs. Ther Drug Monitor 17 564-569. 

Kiessig et al. studied the interaction of the immunosuppressant drug cyclosporin A and some derivatives to its cellular receptor protein cyclo-philin (26). The cyclophilin-cyclosporin A complex mediates the immunosuppressive action of cyclosporin A by inhibition of the phosphatase calci-neurin. Using ACE in the equilirium-mixture mode, a separation of the cyclophilin-cyclosporin A complex and the unbound cyclophilin was achieved. The approach allowed a qualitative estimation of the binding affinity of cyclosporin A derivatives compared to cyclosporin A. For the calculation of binding constants, electrophoretically mediated microanalysis was applied. 

Cytotoxic and immunosuppressive drugs, which inhibit the synthesis or action of crucial cellular macromolecules, such as nucleic acids, are used in three broad categories of skin disease hyperproUferative disorders, such as psoriasis immunological disorders, such as autoimmune bullous diseases and skin neoplasms. The pharmacology of these drugs is discussed in Chapter 57. 

Many immunosuppressive drugs act by reducing lymphocyte proliferation during the induction phase of the immune response, but some also have inhibitory actions on the effector phase. They can be classified according to their modes of action ... 

Azathioprine is a prodrug of mercaptopurine and, like mercaptopurine, functions as an antimetabolite (see Chapter 54). Although its action is presumably mediated by conversion to mercaptopurine and further metabolites, it has been more widely used than mercaptopurine for immunosuppression in humans. These agents represent prototypes of the antimetabolite group of cytotoxic immunosuppressive drugs, and many other agents that kill proliferative cells appear to work at a similar level in the immune response. 

A number of chemicals with demonstrable suppression of immune function produce this action via indirect effects. By and large, the approach that has been most frequently used to support an indirect mechanism of action is to show immune suppression after in vivo exposure but no immune suppression after in vitro exposure to relevant concentrations. One of the most often cited mechanisms for an indirect action is centered around the limited metabolic capabilities of immunocompetent cells and tissues. A number of chemicals have caused immune suppression when administered to animals but were essentially devoid of any potency when added directly to suspensions of lymphocytes and macrophages. Many of these chemicals are capable of being metabolized to reactive metabolites, including dime-thylnitrosamine, aflatoxin Bi, and carbon tetrachloride. Interestingly, a similar profile of activity (i.e., suppression after in vivo exposure but no activity after in vitro exposure) has been demonstrated with the potent immunosuppressive drug cyclophosphamide. With the exception of the PAHs, few chemicals have been demonstrated to be metabolized when added directly to immunocompetent cells in culture. A primary role for a reactive intermediate in the immune suppression by dimethylnitrosamine, aflatoxin Bi, carbon tetrachloride, and cyclophosphamide has been confirmed in studies in which these xenobiotics were incubated with suspensions of immunocompetent cells in the presence of metabolic activation systems (MASs). Examples of MASs include primary hepatocytes, liver microsomes, and liver homogenates. In most cases, confirmation of a primary role for a reactive metabolite has been provided by in vivo studies in which the metabolic capability was either enhanced or suppressed by the administration of an enzyme inducer or a metabolic inhibitor, respectively. 

Lee SH, Hahn SJ, Min G et al (2011) Inhibitory actions of HERG currents by the immunosuppressant drug cyclosporin a. Korean J Physiol Pharmacol 15(5) 291-297... 

Similarly, we know from the clinics that it usually takes drastic treatments to compromise the human immune system to result in immunosuppression. Some examples of doses required for immunosuppression of substances developed or known to suppress the immune system in consequence of drug action ... 

The search for a common mechanism of action cf the immunosuppressive drugs cyclosporin (CsA) (7)and FK-506 (8)highlights another possibility in which the drug was I discovaed by screening in cellular or in vivo models but the exact mechanism or site of I action is unknown (157). Using the active mol-I ecules, cyclophilin (CyP) and the FK binding protein (FKBP)were identified as the specific receptors for cyclosporin and FK-506, respec-I lively. These binding proteins were discovered to be distinct and inhibitor-specific cis-trans peptidyl-prolyl isomerases that catalyze the... 

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