Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

DRUGS WITH IMMUNOSUPPRESSIVE EFFECTS
Treg
Antigen
APC
Th2
B
Humoral
immunity
PC
NK
CD8
Th1
M
Antibody
Target cell
MC
Complement
Cell-mediated
immunity
IL-1
TNF-α
IL-6
Inflammation
Fig. 12.1 A summary of the cellular events leading to production of a humoral or cell-mediated immune response.
Immunomodulatory agents may act at different points within these pathways. Black arrows represent cell signaling
via cytokines. APC, antigen-presenting cell; B, B lymphocyte; IL-1, interleukin 1; IL-6, interleukin 6; M, macrophage;
MC, mast cell; NK, natural killer cell; Th1, Th2, CD8, T lymphocytes; PC, plasma cell; TNF-a, tumor necrosis factor a.
immune-mediated thrombocytopenia, autoimmune
skin diseases such as erythema multiforme and pemphigus,
inflammatory bowel disease, immune-mediated
polyarthritis, anal furunculosis and uveodermatological
syndrome. In addition, azathioprine has been used
experimentally to prevent transplant rejection in
dogs, most commonly as part of multicomponent treatment
with ciclosporin, prednisone and antithymocyte
serum. Use of azathioprine may not be indicated
in acute antibody-mediated diseases as it does not
decrease serum immunoglobulin except indirectly by
inhibiting the function of T-helper cells. The onset of
the immunosuppressive effects of azathioprine may be
delayed (2–4 weeks) so this agent should be administered
from the outset of any immunosuppressive
protocol.
Mechanism of action
Azathioprine is an imidazole prodrug of 6-mercaptopurine,
an established clinical agent for human leukemia.
Azathioprine was developed to overcome the rapid inactivation
of 6-mercaptopurine by a number of processes
including enzymatic S-methylation, nonenzymatic oxidation
or conversion to 6-thiourate by xanthine oxidase.
6-Mercaptopurine, an analog of the natural purine
hypoxanthine, is converted to mercaptopurinecontaining
nucleotides. This leads to inhibition of purine
synthesis or anabolism to thioinosine monophosphate
(thio-IMP), a fraudulent nucleotide that interferes with
the salvage pathway of purine synthesis. Thio-IMP is
converted to thioguanosine monophosphate (thio-GMP)
and further phosphorylated to thioguanosine triphosphate
(thio-GTP), which causes DNA damage upon
intercalation into the DNA backbone. Azathioprine
may thus inhibit RNA and DNA synthesis and disrupt
mitosis and cellular metabolism.
Azathioprine modulates cell-mediated immunity and
T lymphocyte-dependent antibody synthesis. In a canine
experimental study, azathioprine alone had no significant
effect on serum immunoglobulin concentrations or
the numbers of blood T or B lymphocytes although the
drug was only administered for a 2-week period, reinforcing
the need for longer term administration and
observations.
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