12 Other aspects of their use, generic products, therapeutic drug
monitoring, and adverse effects will be addressed later in this chapter (Case 34-7,
Prednisone, methylprednisolone, and prednisolone—all synthetic analogs of
hydrocortisone—are the primary corticosteroids used to prevent and treat rejection
of transplanted organs. These agents usually are given in fixed doses or dosing is
based on body weight (mg/kg) despite the pharmacokinetic differences. Although they
are an important part of immunosuppression, a goal of most transplantation programs
is to minimize, eliminate, or avoid corticosteroid use because of their numerous and
Corticosteroids have multiple effects on most cells and tissues of the body, but it is
their anti-inflammatory and, more importantly, their immunosuppressive properties
that serve as the basis for their use in organ transplant recipients. The corticosteroids
bind with specific intracellular glucocorticoid receptors and interfere with RNA and
DNA synthesis as well as transcription of specific genes. Cell function is altered,
resulting in suppression or activation of gene transcription. Corticosteroids also
affect RNA translation, protein synthesis, cytokine production and secretion, and
protein and cytokine receptor expression.
Even after a single dose, corticosteroids cause marked lymphocytopenia by
redistribution of circulating lymphocytes to other lymphoid tissues, such as the bone
marrow, rather than by cell lysis; however, they also transiently increase the number
of peripherally circulating neutrophils. Corticosteroids inhibit IL-1 and IL-6
production fromAPC, a number of events associated with T-cell activation, and IL-2
and IFN-γ production. They interfere with the action of IL-2 and IL-2R on activated
T cells, resulting in the inhibition of TH1
function. They can enhance IL-10 regulatory
function and enhance TH2 cell function. Moderate-dose to high-dose corticosteroids
also inhibit cytotoxic T-cell function by inhibiting cytokine production and lysis of T
cells. They can inhibit early proliferation of B cells but have a minimal effect on
activated B cells and immunoglobulin-secreting plasma cells. The corticosteroids
affect most cells and substances associated with acute allograft rejection and
inflammatory reactions. They inhibit accumulation of leukocytes at sites of
inflammation; inhibit macrophage functions, including migration and phagocytosis;
inhibit expression of class II MHC antigens induced by INF-γ; block release of IL-1,
IL-6, and TNF; inhibit the upregulation and expression of costimulatory molecules
and neutrophil adhesion to endothelial cells; inhibit secretion of complement protein
C3; inhibit phospholipase A2 activity; and decrease production of prostaglandins.
The activity of cyclosporine is mediated through a reversible inhibition of T-cell
function, particularly TH cells. Its major effect is inhibiting the production of IL-2
and other cytokines, including INF-γ. These actions result in an inhibition of the early
events of T-cell activation, sensitization, and proliferation. Cyclosporine has little
effect on activated mature cytotoxic T cells. Therefore, it has little usefulness in the
treatment of acute rejection. Its site of action is within the cytoplasm of T cells after
antigenic recognition and signaling occurs. Cyclosporine binds to an intracellular
protein (immunophilin) called cyclophilin. Although binding to cyclophilin is
required, it alone is not sufficient for immunosuppression. This cyclosporine–
cyclophilin complex then binds to a protein phosphatase, calcineurin. This is thought
to prevent activation of nuclear factors involved in the gene transcription for IL-2 and
other cytokines, including IFN. Also, because of this inhibition, cyclosporine
indirectly impairs the activity of other cells, macrophages, monocytes, and B cells in
the immune response. Cyclosporine has no effect on hematopoietic cells or
neutrophils. Cyclosporine is metabolized extensively in the liver to more than 25
metabolites. Two of these metabolites elicit a lower immunosuppressive effect in
vitro. The role of these metabolites in the development of toxicity with cyclosporine
14 The pharmacokinetics, dosing, and therapeutic drug monitoring (TDM)
of cyclosporine are described in Case 34-3, Question 1 and Case 34-4.
Tacrolimus is a macrolide with a different molecular structure than cyclosporine.
Tacrolimus is more effective than cyclosporine in liver and kidney transplant
recipients as the primary immunosuppressant in combination with corticosteroids or
azathioprine, mTOR inhibitors, and antibodies. It also is effective in some patients as
rescue treatment in liver and kidney recipients experiencing acute or chronic
rejection resulting from failure of standard immunosuppressive therapy. Tacrolimus
is the preferred CNI over cyclosporine in most transplant centers.
The activity of tacrolimus is similar to that of cyclosporine, but the concentrations
of tacrolimus needed to inhibit production of IL-2 are 10 to 100 times lower than
those of cyclosporine. Tacrolimus also inhibits production of other cytokines,
although different, protein: FK binding protein 12. This protein, which interacts with
calcineurin, inhibits gene transcription of cytokines and interferes with T-cell
15 The pharmacokinetics, dosing, and TDM of tacrolimus are described in
Sirolimus, formerly known as rapamycin, is an FDA-approved agent for prevention
of acute rejection and for withdrawal of cyclosporine in kidney transplantation.
Positive results for sirolimus also have been observed in other transplant
populations; in situations in which it is used in combination with other agents,
including antibodies, tacrolimus, mycophenolate and prednisone; and when it has
been used for rescue therapy. Its major use is in CNI avoidance, withdrawal, or
Unlike CNIs, which work earlier in the T-cell activation cycle and inhibit cytokine
production, sirolimus is an inhibitor of late T-cell activation. It does not block
cytokine production; rather, it inhibits signal transduction, which blocks the response
of T cells and B cells to cytokines, such as IL-2. Sirolimus binds to the same
immunophilin bound by tacrolimus, FK binding protein. This complex interferes with
the action of certain enzymes or proteins involved in cell proliferation signaling.
Both cyclosporine and tacrolimus inhibit calcineurin, whereas sirolimus influences a
protein called the mammalian target of rapamycin (mTOR). Sirolimus also inhibits an
enzyme called P7056 protein kinase, which is involved in microsomal protein
synthesis. These effects result in cell-cycle arrest, blockage of messenger RNA
production, and blockage of cell proliferation. Sirolimus also inhibits proliferation
of smooth muscle cells and may, although it is too early to tell, reduce the
development of chronic rejection and, potentially, cancer.
Sirolimus exhibits significant pharmacokinetic variability. Its average
bioavailability is 15%; Cmax and AUC are linear over a wide range of doses.
Sirolimus is extensively distributed. It distributes primarily into red blood cells and
is highly plasma protein-bound, approximately 92%. It also binds to lipoproteins.
Sirolimus is extensively metabolized in the gut and liver by cytochrome P-450 3A4
isoenzymes, and it is a substrate for P-glycoprotein. Its drug interaction profile is
similar to that of cyclosporine and tacrolimus. Renal elimination accounts for 2% of
a dose. The terminal half-life is approximately 57 to 63 hours and the time to steady
state is 10 to 14 days in adults and shorter in children.
Everolimus is the newest FDA-approved mTOR inhibitor for use in both kidney
and liver transplantation. Its mechanism of action is similar to sirolimus. Like
sirolimus, it is used in CNI avoidance, withdrawal, or minimization protocols.
Everolimus is hepatically metabolized through the cytochrome P-450 3A4 but has
a shorter half-life, average 30 hours, and different dose and frequency schedule than
sirolimus. Similar to sirolimus, it requires monitoring of trough blood concentrations,
although the target range is different from sirolimus. Its role in transplantation is
generally similar to sirolimus, but direct comparison to sirolimus is needed.
Aspects of its use are discussed in Case 34-4, Question 2.
This agent is the first FDA-approved intravenous (IV) maintenance agent. Belatacept
degree than CD28, resulting in inhibition of costimulation and T-cell activation.
Belatacept is given once every few weeks in combination with other agents, such as
mycophenolate and prednisone, and generally well tolerated. It has been used as
initial therapy, or for CNI avoidance or withdrawal (conversion) to reduce
development or progression of CNI-induced reduction in renal function. Benefits on
renal function have been demonstrated as well as other CNI-associated adverse
effects. However, it should be noted that there is an increased risk of acute rejection,
when belatacept is used in combination with mycophenolate, as compared to a
cyclosporine- and mycophenolate-based regimen. There are no large-scale studies
comparing it to tacrolimus-based regimens or in combination with cytolytic induction
therapy. In clinical practice, some transplant centers utilize belatacept as a
conversion agent in patients that cannot tolerate CNIs. There is an ongoing
multicenter study to assess the efficacy of this. Other small studies have been
published that utilize belatacept with mTOR therapy. It should be noted that
belatacept is contraindicated in patients who are EBV antibody negative, due to risk
of post-transplant lymphoproliferative disorder (PTLD). The phase III studies that
demonstrated a higher risk of PTLD in those that received belatacept noted this was
only the case in EBV-naive recipients, and CNS PTLD was of particular concern.
Recent data presented in abstract form, which followed patients from the phase III
studies out for greater than 7 years post-transplant, have now demonstrated improved
graft survival in the belatacept arm, as compared to the cyclosporine group. Thus,
this agent may offer beneficial outcomes for certain low-risk kidney transplant
recipients. Use in other organs, particularly liver transplant recipients, is not
recommended, due to previous studies demonstrating inferior outcomes, as compared
Polyclonal antibody products have been used for decades to prevent and treat acute
rejection. Polyclonal products used today are administered IV and include equine
(lymphoglobulin) and rabbit antithymocyte globulin, which is considered the
polyclonal antibody of choice.
Antithymocyte globulin (ATG) preparations have also been made in goats and
sheep for investigational study. However, the following discussion is limited to the
products produced in horses and rabbits. Regardless of the species from which they
are produced, all ATG products have similar pharmacologic effects. Their potency
and antibody specificity vary, however, from batch to batch and between products.
The production of polyclonal equine or rabbit antibody begins with the injection of
homogenized human spleen or thymus preparations into the animals. This injection
induces an immune response in the animals directed against human T lymphocytes;
serum containing antibodies to T cells is collected from the animals and purified.
Other antibodies to human cells are produced as well, however. These antibodies
bind to all normal blood mononuclear cells
in addition to T lymphocytes and B lymphocytes, resulting in depletion of
lymphocytes, platelets, and leukocytes from the peripheral circulation. The
mechanism of action of these agents is thought to be linked to lysis of peripheral
lymphocytes, uptake of lymphocytes by the reticuloendothelial system, masking of
lymphocyte receptors, apoptosis, and immunomodulation. These agents contain
antibodies to a number of cell-surface markers on lymphocytes, including CD2, CD3,
CD4, CD8, CD11a, CD25, CD44, CD45, HLA-DR, and HLA class I antigens. They
also interfere with leukocyte adhesion and trafficking and also have effects against
+ B cells. ATG preparations can produce a rapid and profound depletion of
circulating T cells, often within 24 hours of the initial dose. The duration of the effect
can last several weeks after a course of therapy, particularly with rabbit
antithymocyte globulin. Antibodies can be produced to these products as well. This,
however, does not appear to influence clinical outcomes (see Case 34-1).
Basiliximab is an IL-2R antagonist, monoclonal antibody approved for use in
combination with other immunosuppressives to prevent acute cellular rejection in
kidney transplantation. Basiliximab is a chimeric antibody that contains both murine
and human antibody sequences. This agent prevents episodes of acute rejection in
kidney transplant recipients. It has been used, although not as frequently, in liver
transplants. Comparative studies between basiliximab and other antibodies, such as
rabbit antithymocyte globulin, have been conducted. Advantages over these other
agents include ease of administration, minimal side effects, low immunogenicity, no
greater infections or malignancy rates, and fewer required doses. It is well tolerated,
although there are rare reports of anaphylaxis. Basiliximab appears to be most
effective in immunologically low-risk patients, whereas in high-risk patients, its use
may be limited. It binds to the α-subunit of the IL-2R, also known as CD25 or the
TAC subunit, which is expressed only on the surface of activated T cells; this subunit
is critical to IL-2 activation of T cells in the acute rejection process. Basiliximab
prevents the IL-2R from binding with IL-2, thereby blocking T-cell activation. It does
not cause lymphocyte depletion. Basiliximab, with the two-dose IV regimen, on days
0 and 4 post-transplant, saturates the receptor for approximately 30 to 50 days in
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