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Immunosuppressive drugs: the first 50 years and a glance forward.
Allison AC.
Immunopharmacology. 2000 May;47(2-3):63-83.
SurroMed Corporation, 1060 E. Meadow Circle, Palo Alto, CA 94303,
During the past 50 years, many immunosuppressive drugs have been described.
Often their mechanisms of action were established long after their discovery.
Eventually these mechanisms were found to fall into five groups:
(i) regulators of gene expression;
(ii) alkylating agents;
(iii) inhibitors of de novo purine synthesis;
(iv) inhibitors of de novo pyrimidine synthesis; and
(v) inhibitors of kinases and phosphatases.
Glucocorticoids exert immunosuppressive and anti-inflammatory activity mainly
by inhibiting the expression of genes for interleukin-2 and other mediators.
Cyclophosphamide metabolites alkylate DNA bases and preferentially suppress
immune responses mediated by B-lymphocytes.
Methotrexate and its polyglutamate derivatives suppress inflammatory responses
through release of adenosine; they suppress immune responses by inducing the
apoptosis of activated T-lymphocytes and inhibiting the synthesis of both purines
and pyrimidines.
Azathioprine metabolites inhibit several enzymes of purine synthesis.
Mycophenolic acid and Mizoribine inhibit inosine monophosphate
dehydrogenase, thereby depleting guanosine nucleotides. Mycophenolic acid
induces apoptosis of activated T-lymphocytes.
A Leflunomide metabolite and Brequinar inhibit dihydroorotate dehydrogenase,
thereby suppressing pyrimidine nucleotide synthesis.
Cyclosporine and FK-506 (Tacrolimus) inhibit the phosphatase activity of
calcineurin, thereby suppressing the production of IL-2 and other cytokines.
In addition, these compounds have recently been found to block the JNK
and p38 signaling pathways triggered by antigen recognition in T-cells.
In contrast, Rapamycin inhibits kinases required for cell cycling and responses to
IL-2. Rapamycin also induces apoptosis of activated T-lymphocytes.
Immunosuppressive and anti-inflammatory compounds in development include
inhibitors of p38 kinase and of the type IV isoform of cyclic AMP
phosphodiesterase which is expressed in lymphocytes and monocytes.