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

In a large phase II clinical trial, belatacept was administered intravenously
initially every 2 weeks then every 4 or 8 weeks without
calcineurin inhibitors and compared to a cyclosporine-based regimen
(Vincenti et al., 2005). Belatacept showed comparable efficacy
to cyclosporine but was associated with better renal function. Recent
reports from phase III trials show similar results to phase II except
that the more intense regimen was no more efficacious than the lower
intensity regimen but was associated with more infections and posttransplant
lymphoproliferative disease (PTLD) (Emamaullee et al.,
2009). Because of the risk of PTLD, EBV negative patients should
not be treated with belatacept. Belatacept may be approved for maintenance
biologic therapy in renal transplantation soon.
A second co-stimulatory pathway involves the interaction of
CD40 on activated T cells with CD40 ligand (CD154) on B cells,
endothelium, and/or antigen-presenting cells (Figure 35–4). Among
the purported activities of anti-CD154 antibody treatment is the
blockade of B7 expression induced by immune activation. Two
humanized anti-CD154 monoclonal antibodies have been used in
clinical trials in renal transplantation and auto-immune diseases. The
development of these antibodies, however, is on hold because of
associated thromboembolic events. An alternative approach to block
the CD154-CD40 pathway is to target CD40 with monoclonal antibodies.
These antibodies are undergoing trials in non-Hodgkin’s
lymphoma but are also likely to be developed for auto-immunity and
transplantation.
Donor Cell Chimerism
Another promising approach is induction of chimerism (co-existence
of cells from two genetic lineages in a single individual) by any of
a variety of protocols that first dampen or eliminate immune function
in the recipient with ionizing radiation, drugs such as cyclophosphamide,
and/or antibody treatment and then provide a new source
of immune function by adoptive transfer (transfusion) of bone marrow
or hematopoietic stem cells (Starzl et al., 1997). Upon reconstitution
of immune function, the recipient no longer recognizes new
antigens provided during a critical period as “nonself.” Such tolerance
is long lived and is less likely to be complicated by the use of
calcineurin inhibitors. Although the most promising approaches in
this arena have been therapies that promote the development of
mixed or macrochimerism, in which substantial numbers of donor
cells are present in the circulation, some microchimerization
approaches also have shown promise in the development of longterm
unresponsiveness.
Soluble HLA
In the pre-cyclosporine era, blood transfusions were shown to be
associated with improved outcomes in renal transplant patients
(Opelz and Terasaki, 1978). These findings gave rise to donorspecific
transfusion protocols that improved outcomes (Opelz et al.,
1997). After the introduction of cyclosporine, however, these effects
of blood transfusions disappeared, presumably due to the efficacy
of this drug in blocking T-cell activation. Nevertheless, the existence
of tolerance-promoting effects of transfusions is irrefutable. It is possible
that this effect is due to HLA molecules on the surface of cells
or in soluble forms. Recently, soluble HLA and peptides corresponding
to linear sequences of HLA molecules have been shown to
induce immunological tolerance in animal models via a variety of
mechanisms (Murphy and Krensky, 1999).
Antigens
Specific antigens provided in a variety of forms (generally as peptides)
induce immunological tolerance in preclinical models of diabetes mellitus,
arthritis, and MS. Clinical trials of such approaches are under
way. The past decade has witnessed a revolution in our understanding
of the basis of immune tolerance. It is now well established that antigen/MHC
complex binding to the T cell–receptor/CD3 complex coupled
with soluble and membrane-bound co-stimulatory signals
initiates a cascade of signaling events that lead to productive immunity.
In addition, the immune response is regulated by a number of negative
signaling events that control cell survival and expansion. In vitro and
preclinical in vivo studies have demonstrated that one can selectively
inhibit immune responses to specific antigens without the associated
toxicity of established immunosuppressive therapies (Van Parijs and
Abbas, 1998). With these insights comes the promise of specific
immune therapies to treat the vast array of immune disorders from
auto-immunity to transplant rejection. These new therapies will take
advantage of a combination of drugs that target the primary
T-cell receptor–mediated signal, either by blocking cell-surface receptor
interactions or inhibiting early signal transduction events. The drugs
will be combined with therapies that effectively block co-stimulation to
prevent cell expansion and differentiation of those cells that have
engaged antigen while maintaining a non-inflammatory milieu.
IMMUNOSTIMULATION
General Principles
In contrast to immunosuppressive agents that inhibit the
immune response in transplant rejection and autoimmunity,
a few immunostimulatory drugs have been
developed with applicability to infection, immunodeficiency,
and cancer. Problems with such drugs include
systemic (generalized) effects at one extreme or limited
efficacy at the other.
Immunostimulants
Levamisole. Levamisole (ERGAMISOL) was synthesized originally as
an anthelmintic but appears to “restore” depressed immune function
of B lymphocytes, T lymphocytes, monocytes, and macrophages. Its
only clinical indication was as adjuvant therapy with 5-fluorouracil
after surgical resection in patients with Dukes’ stage C colon cancer
(Moertel et al., 1990). Because of its risk for fatal agranulocytosis,
levamisole was withdrawn from the U.S. market in 2005.
Thalidomide. Thalidomide (THALOMID) is best known
for the severe, life-threatening birth defects it caused
when administered to pregnant women. For this reason,
it is available only under a restricted distribution program
and can be prescribed only by specially registered
physicians who understand the risk of teratogenicity if
thalidomide is used during pregnancy. Thalidomide
should never be taken by women who are pregnant or
who could become pregnant while taking the drug.
Nevertheless, it is indicated for the treatment of patients
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CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS