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, USA.
(Note, - this document does
not
address "targeted" monoclonal antibody biological" drugs that
selectively modify specific parts of the inflammation process of the
immune system.)
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.
Gene
Expression - Glucocorticoids exert
immunosuppressive and anti-inflammatory activity mainly by inhibiting
the expression of genes for interleukin-2 and other mediators.
Alkylating
Agents - Cyclophosphamide metabolites alkylate
DNA bases and preferentially suppress immune responses mediated by
B-lymphocytes.
Inhibitors
of purine synthesis
- 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.
Inhibitors
of kinases and phosphatases
- 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.
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