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

of mAbs and the introduction of the murine anti-CD3 mAb
(muromonab-CD3 or OKT3) (Ortho Multicenter Transplant Study
Group, 1985). ATG is the most frequently used depleting agent.
Lymphocyte immune globulin and OKT3 are rarely used because of
poorer efficacy and acute side effects, respectively. Alemtuzumab, a
humanized anti-CD52 monoclonal antibody that produces prolonged
lymphocyte depletion, is approved for use in chronic lymphocytic
leukemia but is increasingly used off label as induction therapy in
transplantation.
In many transplant centers, induction therapy with biological
agents is used to delay the use of the nephrotoxic calcineurin
inhibitors or to intensify the initial immunosuppressive therapy in
patients at high risk of rejection (i.e., repeat transplants, broadly presensitized
patients, African-American patients, or pediatric patients).
Most of the limitations of murine-based mAbs generally were overcome
by the introduction of chimeric or humanized mAbs that lack
antigenicity and have a prolonged serum t 1/2
. Antibodies derived
from transgenic mice carrying human antibody genes are labeled
“humanized” (90-95% human) or “fully human” (100% human);
antibodies derived from human cells are labeled “human.” However,
all three types of antibodies probably are of equal efficacy and safety.
Chimeric antibodies generally contain ~33% mouse protein and 67%
human protein and can still produce an antibody response, resulting
in reduced efficacy and t 1/2
compared to humanized antibodies. The
anti–IL-2R mAbs (frequently referred to as anti-CD25) were the first
biologicals proven to be effective as induction agents in randomized
double-blind prospective trials (Vincenti et al., 1998).
Biological agents for induction therapy in the prophylaxis of
rejection currently are used in ~70% of de novo transplant patients
and have been propelled by several factors, including the introduction
of the relatively safe anti–IL-2R antibodies and the emergence of
ATG as a safer and more effective alternative to lymphocyte immune
globulin or muromonab-CD3. Biologicals for induction can be
divided into two groups: the depleting agents and the immune modulators.
The depleting agents consist of lymphocyte immune globulin,
ATG, and muromonab-CD3 mAb (the latter also produces
immune modulation); their efficacy derives from their ability to
deplete the recipient’s CD3-positive cells at the time of transplantation
and antigen presentation. The second group of biological agents,
the anti–IL-2R mAbs, do not deplete T lymphocytes, with the possible
exception of T regulatory cells, but rather block IL-2–mediated
T-cell activation by binding to the α chain of IL-2R.
More aggressive approaches have been recently utilized in
patients with high levels of anti-HLA antibodies, donor-specific antibodies
detected by cytotoxicity cross-match, or flow cytometry and
humoral rejection. These therapies include plasmapheresis, intravenous
immunoglobulin, and rituximab, a chimeric anti-CD20 monoclonal
antibody (Akalin et al., 2003; Zachary et al., 2003; Vo et al., 2008).
Maintenance Immunotherapy. The basic immunosuppressive protocols
use multiple drugs simultaneously. Therapy typically involves
a calcineurin inhibitor, glucocorticoids, and mycophenolate (a purine
metabolism inhibitor; see “Mycophenolate Mofetil”), each directed
at a discrete site in T-cell activation (Suthanthiran et al., 1996).
Glucocorticoids, azathioprine, cyclosporine, tacrolimus, mycophenolate,
sirolimus, and various monoclonal and polyclonal antibodies
all are approved for use in transplantation. Glucocorticoid-free regimens
have achieved special prominence in recent successes in using
pancreatic islet transplants to treat patients with type I diabetes mellitus.
Protocols employing rapid steroid withdrawal (within 1 week
after transplantation) are being utilized in more than a third of renal
transplant recipients. Short-term results are good, but the effects on
long-term graft function are unknown (Vincenti et al., 2008). Recent
data suggest that calcineurin inhibitors may shorten graft t 1/2
by their
nephrotoxic effects (Nankivell et al., 2003). Protocols under evaluation
include calcineurin dose reduction or switching from calcineurin to
sirolimus-based immunosuppressive therapy at 3-4 months.
Therapy for Established Rejection. Although low doses of prednisone,
calcineurin inhibitors, purine metabolism inhibitors, or
sirolimus are effective in preventing acute cellular rejection, they are
less effective in blocking activated T lymphocytes and thus are not
very effective against established, acute rejection or for the total prevention
of chronic rejection (Monaco et al., 1999). Therefore, treatment
of established rejection requires the use of agents directed against
activated T cells. These include glucocorticoids in high doses (pulse
therapy), polyclonal antilymphocyte antibodies, or muromonab-CD3.
Adrenocortical Steroids
The introduction of glucocorticoids as immunosuppressive
drugs in the 1960s played a key role in making
organ transplantation possible. Their chemistry, pharmacokinetics,
and drug interactions are described in
Chapter 42. Prednisone, prednisolone, and other glucocorticoids
are used alone and in combination with other
immunosuppressive agents for treatment of transplant
rejection and auto-immune disorders.
Mechanism of Action. The immunosuppressive effects
of glucocorticoids have long been known, but the specific
mechanisms of their immunosuppressive actions somewhat
elusive. Glucocorticoids lyse (in some species) and
induce the redistribution of lymphocytes, causing a rapid,
transient decrease in peripheral blood lymphocyte counts.
To effect longer-term responses, steroids bind to receptors
inside cells; either these receptors, glucocorticoidinduced
proteins, or interacting proteins regulate the
transcription of numerous other genes (Chapter 42).
Additionally, glucocorticoids curtail activation of NF-κB,
which increases apoptosis of activated cells (Auphan et
al., 1995). Of central importance, key pro-inflammatory
cytokines such as IL-1 and IL-6 are downregulated. T
cells are inhibited from making IL-2 and proliferating.
The activation of cytotoxic T lymphocytes is inhibited.
Neutrophils and monocytes display poor chemotaxis and
decreased lysosomal enzyme release. Therefore, glucocorticoids
have broad anti-inflammatory effects on multiple
components of cellular immunity. In contrast, they
have relatively little effect on humoral immunity.
Therapeutic Uses. There are numerous indications for
glucocorticoids. They commonly are combined with
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CHAPTER 35
IMMUNOSUPPRESSANTS, TOLEROGENS, AND IMMUNOSTIMULANTS