DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

the treatment of polyomavirus nephropathy seen in
immunosuppressed renal transplant recipients. There are
no controlled studies showing efficacy compared with control
patients treated with only withdrawal or reduction of
immunosuppression alone in BK virus nephropathy. The
drug inhibits dihydroorotate dehydrogenase in the de novo
pathway of pyrimidine synthesis. It is hepatotoxic and can
cause fetal injury when administered to pregnant women.
Fingolimod (FTY720). This is the first agent in a new class of small
molecules, sphingosine-1-phosphate receptor (S1P-R) agonists
(Figure 35–1). This S1P receptor prodrug reduces recirculation of
lymphocytes from the lymphatic system to the blood and peripheral
tissues, including inflammatory lesions and organ grafts.
Therapeutic Uses. The drug has not been as effective as standard
regimens in phase III trials, and further drug development has been
limited (Vincenti and Kirk, 2008).
Mechanism of Action. Unlike other immunosuppressive agents,
FTY720 acts via “lymphocyte homing.” It specifically and reversibly
sequesters host lymphocytes into the lymph nodes and Peyer’s
patches and thus away from the circulation. This protects the graft
from T cell–mediated attack. Although FTY720 sequesters lymphocytes,
it does not impair either T- or B-cell functions. FTY720 is
phosphorylated by sphingosine kinase-2, and the FTY720-phosphate
product is a potent agonist of S1P receptors. Altered lymphocyte
traffic induced by FTY720 clearly results from its effect on S1P
receptors.
Myeloma
cell culture HPRT - lg -
Myeloma Cells
Flask
Immunization
Expand hybridoma,
test supernatant
Flask
HPRT + lg +
Spleen/Lymph Node Cells
Toxicity. Lymphopenia, the most common side effect of FTY720,
is predicted from its pharmacological effect and is fully reversible
upon drug discontinuation. Of greater concern is the negative
chronotropic effect of FTY720 on the heart, which has been
observed with the first dose in up to 30% of patients. In most
patients, the heart rate returns to baseline within 48 hours, with the
remainder returning to baseline thereafter.
Biological Immunosuppression
Antibodies and Fusion Receptor Protein
Both polyclonal and monoclonal antibodies against lymphocyte
cell-surface antigens are widely used for prevention
and treatment of organ transplant rejection.
Polyclonal antisera are generated by repeated injections
of human thymocytes (ATG) or lymphocytes (antilymphocyte
globulin, ALG) into animals such as horses,
rabbits, sheep, or goats and then purifying the serum
immunoglobulin fraction. Although highly effective
immunosuppressive agents, these preparations vary in
efficacy and toxicity from batch to batch. The advent of
hybridoma technology to produce monoclonal antibodies
was a major advance in immunology (Kohler and
Milstein, 1975). It now is possible to make essentially
unlimited amounts of a single antibody of a defined
specificity (Figure 35–3). These monoclonal reagents
Fusion in
polyethylene
glycol
Select hybrid
cells in HAT
medium
and clone
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CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS
Freeze hybridoma
for future use
Freezer
Make ascites and purify
monoclonal antibody
Expansion
Screen for
antibody-secreting
clones of interest
and reclone
Figure 35–3. Generation of monoclonal antibodies. Mice are immunized with the selected antigen, and spleen or lymph node is harvested
and B cells separated. These B cells are fused to a suitable B-cell myeloma that has been selected for its inability to grow in
medium supplemented with hypoxanthine, aminopterin, and thymidine (HAT). Only myelomas that fuse with B cells can survive in
HAT-supplemented medium. The hybridomas expand in culture. Those of interest based on a specific screening technique are then
selected and cloned by limiting dilution. Monoclonal antibodies can be used directly as supernatants or ascites fluid experimentally
but are purified for clinical use. HPRT, hypoxanthine–guanine phosphoribosyl transferase. (Reproduced with permission from Krensky
A.M. and Clayberger C. Transplantation immunobiology. In, Pediatric Nephrology, 5th ed. (Avner E.D., Harmon W.E., Niauder P.,
eds) Lippincott Williams & Wilkins, Philadelphia, 2004. (http://lww.com).)