intercellular adhesion molecule (ICAM)-1 found on APCs, which bind with
lymphocyte function-associated antigen expressed on the surface of T cells; ICAM-1
and ICAM-3 on APCs with CD2 on T cells; B7 (now called CD80 and CD86) on
APCs with either CD28 or CTLA4 on T cells; and CD40 on APC with CD40 ligand
(now called CD154) on T cells. The binding of costimulatory molecules is critical to
T-cell activation. Without this costimulation, T cells undergo abortive activation or
programmed T-cell death (apoptosis).
Once recognition and costimulatory binding occurs, T-cell activation and
proliferation are initiated. After interacting with class II antigens and stimulation
from IL-1 secreted from macrophages, TH cells produce and secrete cytokines (e.g.,
interleukin [IL]-2 and interferon [INF]-γ). TH cells are classified according to their
cytokine-secretion pattern into either TH1 or TH2 cells. TH1 cells secrete IL-2, INF,
and tumor necrosis factor (TNF), which stimulate cytotoxic T cells (TC). TH2 cells
secrete IL-4, IL-5, IL-6, IL-10, and IL-13, which stimulate B-cells. TH cells, along
with TC cells, are stimulated to express cell-surface IL-2 receptors (IL-2R) and other
cytokines. Once the TC cells express IL-2R, they bind to IL-2 and other cytokines,
which leads to signal transduction that results in proliferation, division, and
stimulation of T cells (signal 3). These committed TC cells bind directly to
allogeneic cells and produce cell lysis. TH-secreted cytokines recruit other T cells,
which results in further cytotoxicity. During this process, TH cells also produce
cytokines that trigger a cascade of events involving B cells and antibody production,
complement fixation, increased macrophage infiltration, neutrophil involvement,
fibrin deposition, platelet activation and release, prostaglandin release, and
inflammatory response at the graft site. These delayed-type hypersensitivity and
humoral responses occur in conjunction with one another and are not mutually
exclusive. This results in cellular and tissue injury and graft destruction
The antibodies produced by plasma cells, which are transformed B cells under the
influence of cytokines, bind to the target antigenic cells. This leads to local
deposition of complement and results in immune complexation and injury to the graft
(complement-mediated cell lysis). The newly formed antibodies cause a series of
interactions to occur with T cells, which lead to cytotoxicity (antibody-dependent,
cell-mediated cytotoxicity). These cell-mediated and humoral immunologic events
can impair organ function so significantly that without therapeutic intervention,
complete organ graft dysfunction may occur. Under certain circumstances, which are
not clear, certain TC cells, known as suppressor T cells, downregulate the immune
Human Leukocyte Antigen Typing
The genetic compatibility between donor and recipient can have a major impact on
acute rejection, graft function, graft survival, and patient survival. For example, in
kidney transplantation, the closer the HLA matching is between recipient and donor,
the better the outcome, particularly over the long term. To determine this
compatibility, a number of laboratory tests, including serologic, flow cytometric,
genetic-DNA-based, and cellular assessments of donor and recipient serum and
lymphocytes, are performed before organ transplantation. This process is referred to
as tissue typing. Lymphocytes are typed for HLA-A, HLA-B, and HLA-DR. Typing
for HLA is performed using the donor and recipient lymphocytes for serology-based
techniques or tissue or fluid containing nucleated cells.
The panel-reactive antibody (PRA) test is commonly used to assess organ
compatibility because recipients may have HLA antibodies from previous exposure
to antigenic stimuli (e.g., blood transfusions, previous transplantation, and
pregnancy). In this test, the recipient’s serum is tested against a cell panel of known
HLA specificities that are representative of possible donors in the general
population. The percentage of cell reactions (recipient with potential donor)
determines a recipient’s PRA. It is done periodically on patients on the waiting list to
determine their immunologic reactivity. The potential recipient with a higher
percentage of PRA (>20%–50%) is at higher risk for rejection and will generally a
have longer wait time for a kidney than patients with PRA less than 20%. With recent
changes (December 2014) to kidney allocation systems, this wait time may change
A cytotoxic and/or flow cytometry lymphocyte cross-match is also performed
prior to transplantation. In this case, the potential recipient’s serum is cross-matched
to determine whether preformed antibodies to the donor’s lymphocytes are present. A
positive cross-match indicates the presence of recipient cytotoxic IgG antibodies to
the donor. In kidney transplantation, a positive cross-match is usually considered a
contraindication. Recently, a number of transplant programs have utilized
desensitization strategies to reduce the level of HLA antibodies present in potential
recipients as a mechanism to reduce likelihood of a positive cross-match with either
identified living donors or future potential deceased donors. Common strategies to
reduce these preformed HLA antibodies include serial delivery of plasmapheresis
coupled with IVIG, rituximab, and bortezomib.
In liver transplantation, a positive
cross-match is not an absolute contraindication because the need is urgent and
because the liver appears to be more resistant immunologically to this type of
reaction. These liver transplant recipients can, however, experience significant
complications and early graft dysfunction. In kidney transplantation, organ allocation
and matching now utilize a virtual cross-match in which potential recipients are
listed with known unacceptable HLA antigens (those that have been pre-identified in
the patient). If a potential donor is identified with a specific HLA antigen that the
recipient has known antibodies directed against, they will be skipped on the list.
ABO blood typing is one of the most critical of all evaluations when determining
the genetic compatibility for all solid organ transplants. Transplantation of an organ
with ABO incompatibility typically results in a hyperacute rejection and destruction
of the graft, although in kidney transplant, newer therapeutic approaches to overcome
ABO incompatibility have been successful.
Immunosuppressives, based on an improved understanding of their mechanisms of
action and the mechanisms of rejection, have had the most significant impact on
patient and graft survival. The currently used immunosuppressives are shown in
Table 34-1. These agents can be categorized as induction or maintenance therapy.
Sites of action and role of the currently used agents are discussed below.
Azathioprine is a prodrug of 6-mercaptopurine (6-MP). Azathioprine and 6-MP are
purine antagonist antimetabolites. The introduction of cyclosporine, tacrolimus,
mycophenolate, and sirolimus has led to a significant reduction of azathioprine use or
its elimination altogether in immunosuppressive protocols. It can be useful in some
cases, because it is inexpensive, or in patients who cannot tolerate other agents. It
continues to be used in other countries.
Currently Used Immunosuppressive Agents
(How Supplied) Therapeutic Use(s) Major Adverse Effects
Basiliximab (Simulect) IV 20 mg × 2 doses
Everolimus (Zortress) Oral 0.5–1.5 mg BID
sodium succinate (SoluMedrol, various others)
(Rapamune) Oral 2–10 mg/day (0.5-, 1-
Inhibits plasma cells Bone marrow suppression,
Eculizumab (Soliris) 600–1,200 mg IV infusion
Inhibits complement Infusion reaction,
Inhibits B-cell production Infusion reactions ( fever,
Immunomodulation of Tand B cells and/or
Azathioprine, a nonspecific antimetabolite immunosuppressive agent, affects both
cell-mediated (i.e., T cell) and antibody-mediated (i.e., B cell) immune responses.
Because it inhibits the early stages of cell differentiation and proliferation,
azathioprine is useful for preventing rejection, but it is ineffective for the treatment of
acute rejection. 6-MP, an active metabolite, is incorporated into DNA and RNA,
thereby interfering with the intracellular formation of thioguanine nucleotides (TGN).
6-MP is intracellularly converted by hypoxanthine phosphoribosyltransferase to
thioinosinic acid and then to thioguanine nucleotides. 6-MP may have two separate
immunosuppressive effects: inhibition of cellular proliferation and cytotoxicity. A
decrease in the levels of intracellular purine ribonucleotides decreases cellular
proliferation, and incorporation of TGN into DNA mediates cytotoxicity.
The major metabolic conversion of azathioprine to 6-MP is via nucleophilic attack
by glutathione. The liver and red blood cells are thought to be major tissue sites for
this metabolic conversion. The 6-MP formed by this reaction can be metabolized
further to thiopurine ribonucleosides and ribonucleotides such as 6-thioguanine
nucleotide. These active metabolites, which have longer half-lives, are responsible
for immunosuppressive activity. Azathioprine pharmacokinetics are not affected by
renal dysfunction, but 6-TGN metabolite concentrations can accumulate in this
The most common adverse effect of azathioprine is bone marrow suppression.
Bone marrow suppression may be related to a genetic deficiency of the enzyme,
thiopurine methyltransferase. Low activity of this enzyme is rare but in some
leads to greater availability of 6-MP, elevated 6-thioguanine levels, and
susceptibility to myelosuppression. Low levels of thiopurine methyltransferase and
specific genetic polymorphisms of this enzyme have been associated with severe
azathioprine myelotoxicity and reduced efficacy.
10,11 Testing for this polymorphism
has been advocated. However, few transplant centers perform genetic testing prior to
Mycophenolate Mofetil and Mycophenolate Sodium
As a result of several multicenter comparative registry trials in kidney transplant
recipients, mycophenolate mofetil (MMF) has replaced azathioprine in many
transplant protocols. MMF is used as adjunctive therapy in combination with
cyclosporine or tacrolimus, prednisone, mammalian target of rapamycin (mTOR)
inhibitors, and monoclonal and polyclonal antibodies to prevent acute rejection and
used for calcineurin inhibitor (CNI) withdrawal and minimization. It is also used as
rescue therapy when patients have not responded to, or cannot tolerate, the side
effects of other immunosuppressive agents.
MMF is an antiproliferative antimetabolite that inhibits purine synthesis, but in a
more selective manner than azathioprine. Unlike azathioprine, MMF interferes with
the de novo pathway for purine synthesis. MMF is the morpholinoethyl ester prodrug
of mycophenolic acid (MPA), which is the active component. MPA selectively,
noncompetitively, and reversibly blocks an enzyme known as inosine monophosphate
cytokine production. Other secondary effects include inhibition of B-lymphocyte
antibody production, decreased adhesion molecule expression, decreased smooth
muscle proliferation and recruitment, and infiltration of neutrophils
pharmacokinetics are complex and discussed in detail in Case 34-7, Question 9).
Another oral formulation of MPA, enteric-coated mycophenolate sodium, is also
approved by the US Food and Drug Administration (FDA) to prevent rejection in
kidney transplantation, when used in combination with a calcineurin inhibitor (CNI)
and corticosteroids. The original purpose of designing the enteric-coated formulation
was to reduce or prevent the gastrointestinal (GI) side effects commonly seen with
MMF. However, most data suggest that the efficacy rates and side effect profiles of
MMF and mycophenolate sodium are nearly identical. These two agents are not
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