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

1006 the induction and maintenance of immune tolerance, the
active state of antigen-specific nonresponsiveness.
Approaches expected to overcome the risks of infections
and tumors with immunosuppression are reviewed.
These include co-stimulatory blockade, donor-cell
chimerism, soluble HLAs, and antigen-based therapies.
A general discussion of the limited number of immunostimulant
agents is presented, followed by an overview
of active and passive immunization, and concluding
with a brief case study of immunotherapy for MS.
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
IMMUNOSUPPRESSION
Immunosuppressive drugs are used to dampen the
immune response in organ transplantation and autoimmune
disease. In transplantation, the major classes of
immunosuppressive drugs used today are:
• glucocorticoids
• calcineurin inhibitors
• anti-proliferative/antimetabolic agents
• biologicals (antibodies)
These drugs have met with a high degree of clinical
success in treating conditions such as acute immune
rejection of organ transplants and severe auto-immune
diseases. However, such therapies require lifelong use
and nonspecifically suppress the entire immune system,
exposing patients to considerably higher risks of infection
and cancer. The calcineurin inhibitors and glucocorticoids,
in particular, are nephrotoxic and diabetogenic,
respectively, thus restricting their usefulness in a variety
of clinical settings.
Monoclonal and polyclonal antibody preparations
directed at reactive T cells are important adjunct therapies
and provide a unique opportunity to target specifically
immune-reactive cells. Finally, newer small
molecules and antibodies have expanded the arsenal of
immunosuppressives. In particular, mammalian target
of rapamycin (mTOR) inhibitors (sirolimus, everolimus)
and anti-CD25 (interleukin-2 receptor [IL-2R]) antibodies
(basiliximab, daclizumab) target growth-factor pathways,
substantially limiting clonal expansion and thus
potentially promoting tolerance. Immunosuppressive
drugs used more commonly today are described in the
rest of this section. Many more selective therapeutic
agents under development are expected to revolutionize
immunotherapy in the next decade.
General Approach to Organ Transplantation Therapy
Organ transplantation therapy is organized around five general principles.
The first principle is careful patient preparation and selection
Table 35–1
Sites of Action of Selected Immunosuppressive
Agents on T-Cell Activation
DRUG
SITE OF ACTION
Glucocorticoids Glucocorticoid response elements in
DNA (regulate gene transcription)
Muromonab-CD3 T-cell receptor complex (blocks
antigen recognition)
Cyclosporine Calcineurin (inhibits phosphatase
activity)
Tacrolimus Calcineurin (inhibits phosphatase
activity)
Azathioprine DNA (false nucleotide incorporation)
Mycophenolate Inosine monophosphate
mofetil
dehydrogenase (inhibits activity)
Daclizumab, IL-2 receptor (block IL-2-mediated
basiliximab T-cell activation)
Sirolimus Protein kinase involved in cell-cycle
progression (mTOR) (inhibits
activity)
IL, interleukin; mTOR, mammalian target of rapamycin.
of the best available ABO blood type–compatible HLA match for
organ donation. Second, a multitiered approach to immunosuppressive
drug therapy, similar to that in cancer chemotherapy, is
employed. Several agents, each of which is directed at a different
molecular target within the allograft response (Table 35–1; Hong
and Kahan, 2000), are used simultaneously. Synergistic effects permit
use of the various agents at relatively low doses, thereby limiting
specific toxicities while maximizing the immunosuppressive
effect. The third principle is that greater immunosuppression is
required to gain early engraftment and/or to treat established rejection
than to maintain long-term immunosuppression. Therefore,
intensive induction and lower-dose maintenance drug protocols are
employed. Fourth, careful investigation of each episode of transplant
dysfunction is required, including evaluation for rejection, drug toxicity,
and infection, keeping in mind that these various problems can
and often do co-exist. Organ-specific problems (e.g., obstruction in
the case of kidney transplants) also must be considered. The fifth
principle, which is common to all drugs, is that a drug should be
reduced or withdrawn if its toxicity exceeds its benefit.
Biological Induction Therapy. Induction therapy with polyclonal
and monoclonal antibodies (mAbs) has been an important component
of immunosuppression dating back to the 1960s, when Starzl
and colleagues demonstrated the beneficial effect of antilymphocyte
globulin (ALG) in the prophylaxis of rejection in renal transplant
recipients. Over the past 40 years, several polyclonal antilymphocyte
preparations have been used in renal transplantation; however,
only two preparations currently are approved by the FDA for use in
transplantation: lymphocyte immune globulin (ATGAM) and antithymocyte
globulin (ATG; THYMOGLOBULIN) (Howard et al., 1997).
Another important milestone in biological therapy was the development