T-cell activation requires three signals (Figure 2-1).
Signal 1 is initiated by the binding of the alloantigen on the surface of antigenpresenting cell (APC) to the T-cell receptor (TCR)-CD3 complex.
Signal 2 is a non-antigen-specific costimulatory signal provided by the engagement of B7 on the surface of APC with CD28 on T cell. These dual signals (ie, signals 1 and 2) activate the intracellular pathways that trigger T cells to activate interleukin-2 (IL-2) and other growth-promoting cytokines. If a TCR is triggered without the accompanying costimulatory signal 2, then the T cell is driven into an anergic state in which it is both inactivated and refractory to later activation even in the presence of all necessary activation elements.
Signal 3, engagement of IL-2 to its receptor activates the mammalian target of rapamycin (mTOR) pathway to provide signal 3, which leads to cell proliferation.
Lymphocyte proliferation requires the synthesis of purine and pyrimidine nucleotides. Both T and B lymphocytes do not possess the salvage pathway of nucleotide synthesis. As such, these nucleotides must be synthesized de novo.
T cells also express cytotoxic T-lymphocyte antigen-4 (CTLA-4), a cell surface molecule that is homologous to CD28. The binding of B7 to CTLA-4 produces an inhibitory signal that inhibits T-cell proliferation and terminates the immune response. These observations have led to the concept of induction of graft adaptation with agents that target the costimulatory pathways.
Agents targeting both signals 1 and 2
Cyclosporine and tacrolimus are termed calcineurin inhibitors (CNIs) due to their common mechanism of action.
Calcineurin is a phosphatase that dephosphorylates and facilitates the translocation of the nuclear factor of activated T cells (NFAT) (and other nuclear factors) to the nucleus. Once translocated into the nucleus, NFAT promotes the translation of specific genes, including that of the growth promoting cytokine IL-2. Inhibition of calcineurin impairs the expression of IL-2 (and other growth-promoting cytokines), thereby reducing the proliferation of T cells.
Agents targeting signal 2
Belatacept (Nulojix) is a humanized fusion protein, composed of CTLA-4 fused with the Fc domain of human immunoglobulin G1 (CTLA-4Ig). Belatacept binds to B7 with high affinity and inhibits the costimulatory pathway.1
Agents targeting signal 3
Basiliximab is a humanized monoclonal antibody that targets against the chain of the IL-2 receptor (also known as anti-interleukin-2 receptor [anti-IL-2R] or anti-CD25 antibody), blocking IL-2-mediated responses.
Daclizumab (no longer commercially available in the United States)
mTOR inhibitors: sirolimus and everolimus
The mTOR is a key regulatory kinase in the cell division process. Its inhibition reduces cytokine-dependent cellular proliferation at the G1 to S phase of the cell division cycle.
Thymoglobulin is a polyclonal antibody preparation made by immunization of rabbits with human lymphoid tissue. The purified immunosuppressive product contains cytotoxic antibodies directed against a variety of T-cell markers.
Thymoglobulin causes lymphocyte depletion through various mechanisms, including (1) complement-mediated lysis of lymphocytes, (2) lymphocyte uptake by the reticuloendothelial system, and (3) masking lymphocyte cell surface receptors. Thymoglobulin use can result in prolonged lymphopenia, and the CD4+ helper T-lymphocyte subsets may be suppressed for several years. Such prolonged immunosuppressive effect may prevent rejection recurrence.
Thymoglobulin can also cause rapid expansion of the subset of T cells that express CD4+CD25+ and FOXP3+ also known as regulatory T cells (Tregs). Tregs are different from helper T cells in that their presence may limit antigraft immunity. High levels of Tregs increase the chance of reversal of acute rejection.2
Alemtuzumab is a humanized monoclonal antibody targeting against CD52 on the surface of both B and T lymphocytes leading to a rapid and profound depletion of peripheral and central lymphoid cells.
Mycophenolic acid (MPA) derivatives (mycophenolate mofetil [MMF], mycophenolate sodium)
MMF (CellCept) is a prodrug that must be hydrolyzed to the active agent—MPA—in the gastric acidic milieu. MPA is a reversible inhibitor of the enzyme inosine monophosphate dehydrogenase (a rate-limiting enzyme in the de novo synthesis of purines). Depletion of guanosine nucleotides by MPA has a relatively selective antiproliferative effect on lymphocytes due to their reliance on the de novo pathway of nucleotide synthesis.
Mycophenolate sodium (Myfortic) is an enteric-coated formulation of MPA that dissolves at pH >5.5. Therefore, unlike MMF, mycophenolate sodium bypasses the acidic milieu of the stomach and is absorbed in the intestines.
The use of antacids or proton pump inhibitors (PPIs) can reduce the dissolution of MMF by increasing gastric pH. In contrast, the bioavailability of mycophenolate sodium is not affected by antacids or PPIs.
AZA is a precursor of 6-mercaptopurine.
AZA inhibits DNA replication and subsequent T-cell proliferation.
MMF/mycophenolate sodium has largely replaced AZA due to its greater efficacy in reducing acute rejection.
Key component of all immunosuppressive regimens
Modulates inflammatory mediators
Blocks interleukin-1 (IL-1) and IL-2 production, thereby suppressing the early phase of the immune response
calcium channel blocker to boost CNI or mTOR inhibitor levels (Table 2-1). The use of diltiazem or verapamil may permit CNI dose reductions of up to 40% and 30% to 50%, respectively.3
TABLE 2-1 Components of a Standard Immunosuppressive Protocol (Immunosuppressive and Nonimmunosuppressive Agents)
Induction therapy is used to rapidly create a therapeutic net state of immunosuppression in the first few days or week after transplantation in order to prevent rejection.
Induction therapy can be classified into lymphocyte-depleting and non-lymphocytedepleting agents. The choice of one induction agent over the other is generally based on each individual immunologic risk factors or anticipated delayed graft function (DGF) or both (Table 2-2).
In the presence of anticipated DGF due to donor acute tubular necrosis (ATN), it is important to maintain adequate immunosuppression. It has been suggested that endothelial injury upregulates and exposes donor histocompatibility antigens, adhesion molecules, and costimulatory molecules, heightening the risk for acute rejection. Induction therapy with lymphocyte-depleting agent and delayed introduction of CNI may avoid the additive
injury associated with CNI nephrotoxicity (due to afferent arteriolar vasoconstriction) while reducing the risk of allograft rejection at the time of heightened immunogenicity.
TABLE 2-2 Induction Therapy: Lymphocyte-Depleting Versus Non-Lymphocyte-Depleting Agents
Thymoglobulin vs basiliximab induction
Thymoglobulin: commonly used in high immunologic risk patients (eg, highly sensitized or re-allograft transplant recipient, DSA positive) or anticipated delayed graft function to avoid early exposure to cyclosporine or tacrolimus (nephrotoxic)
Basiliximab: commonly used in low to moderate immunologic risk transplant recipients
Alemtuzumab is used at a small number of transplant centers in the United States.
Abbreviation: DSA, donor-specific antibody.
a Lymphocyte-depleting agents can cause first-dose reaction or cytokine release syndrome including chills, fever, arthralgia, and rarely serum sickness.
b No longer commercially available in the United States.
Maintenance immunosuppression is used to sustain a therapeutic net state of immunosuppression in order to prevent rejection.
A standard maintenance immunosuppressive regimen consists of triple drug therapy: CNI (cyclosporine or tacrolimus) + adjunctive agent + corticosteroid.
CNI: The choice of tacrolimus over Cyclosporine A (CSA) or vice versa is generally based on the potential adverse effects of these agents (Table 2-3). See examples in the following text:
Tacrolimus is the preferred agent for women and pediatric patients due to the cosmetic side effects of CSA such as hirsutism or hypertrichosis and gingival hyperplasia.
Cyclosporine is less diabetogenic than tacrolimus,4 and it may be the preferred agent for patients at risk for posttransplantation diabetes mellitus (PTDM) such as those with a strong family history of diabetes or African American race, particularly those with concomitant hepatitis C infection. Risks factors for PTDM are discussed in chapter 14.
CNI switch can be considered due to undesirable side effects. For instance, tacrolimus-treated patients with tremors or hair loss can be switched over to CSA. The starting dose at the time of switching is based on patient’s weight. The evening dose of tacrolimus can be omitted and CSA started the next morning. Concurrent administration of both drugs is not necessary and may increase the risk of nephrotoxicity. Patient’s drug levels should be monitored closely after switching. Patients undergoing CSA to tacrolimus switch can follow similar protocol.
Over the past decade, there has been a steady trend in the United States and Europe toward greater use of tacrolimus (Prograf). Envarsus XR and Astagraf XL are extended-release formulations of tacrolimus.5 Prograf to Envarsus conversion ratio: approximately 1 to 0.75 to 0.80. Phase 3 clinical trial suggested that once-daily extended-release tacrolimus in de novo kidney transplantation has comparable efficacy and safety profile to that of immediate-release tacrolimus twice daily.6
TABLE 2-3 Side Effect Profiles of Cyclosporine and Tacrolimus
CSA > Tac
Hypertension and sodium retention
Hypertension and sodium retention
CSA > Tac
CSA > Tac
Tac > CSA
Neurotoxicity (headache, tremors, confusion, paresthesia)
Neurotoxicity (headache, tremors, confusion, paresthesia, insomnia)
Tac > CSA
Gastrointestinal side effects (hepatotoxicity approximately 4% first month, dose related)
Gastrointestinal side effects (diarrhea, abdominal pain, nausea, vomiting, decreased appetite)
CSA > Tac
TABLE 2-4 Side Effect Profiles of Mycophenolate Mofetil and Mycophenolate Sodium
Mycophenolate mofetil (MMF) CellCept
Mycophenolate sodium (enteric-coated MPA derivative formulation) Myfortic
Diarrhea, nausea, vomiting, abdominal pain, flatulence, dyspepsia
Potentially less gastrointestinal toxicity compared with CellCept
Hematologic effects: leukopenia, leukocytosis (less commonly seen than leukopenia), anemia, thrombocytopenia,
Hematologic effects: leukopenia, leukocytosis (less commonly seen than leukopenia), anemia, thrombocytopenia
Comments: More than 2 g/d is usually not well tolerated.
Comments: Myfortic 180 mg = CellCept 250 mg (similar efficacy)
Abbreviation: MPA, mycophenolic acid.
Adjunctive agent: The MPA derivative MMF (or the enteric-coated mycophenolic sodium salt formulation) is the most commonly used adjunctive agent. The side effect profile of these agents is shown in Table 2-4. AZA, sirolimus, or everolimus is generally used in place of MPA derivatives for special indications.
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