Cyclosporine (CSA) and Tacrolimus (TAC) interfere with the cellular pathway for cytokine production and proliferation. The protein calcineurin has been validated as part of the calcium-dependent signal transduction pathway of interleukin-2 (IL-2) production in T cells. Cyclosporine and Tacrolimus bind to two different intracellular receptors. The resulting receptor complex binds to calcineurin, blocking its phosphatase ability and thereby stopping the production of IL-2 [15].

CSA was isolated from a soil sample in Norway and produced by the fungus Tolypocladium inflatum. The introduction of cyclosporine in the early 1980s dramatically altered the field of transplantation by significantly improving outcomes after kidney transplants. CSA binds to its cytoplasmic receptor protein, cyclophilin A (CypA), which subsequently inhibits the activity of calcineurin. T-cell suppression is a result of a decreased expression of several critical T-cell activation genes, the most important being for IL-2 [16]. The first formulation approved by the US Food and Drug Administration (FDA) was Sandimmune^® (Novartis, Basel, Switzerland), an oil-based formulation, with poor bioavailability and variable absorption. Newer formulations, Gengraf^® (Abbott Laboratories, North Chicago, IL) and Neoral^® (Novartis, Basel, Switzerland), are microemulsified making absorption much more reliable. CSA can be given both intravenously or orally to maintain trough levels of 250–350 ng/mL for the first 3 months posttransplant; it can be then tapered to 150–250 ng/mL [17].

CSA is metabolized by the cytochrome P450 3A4 enzyme system that is not only in the liver but also in the cells lining the intestine, so CSA levels can be increased or decreased by changes in gut absorption or in liver metabolism. The extensive side effect profile of CSA has long been a reason for attempts at minimizing drug exposure. Drug interactions and side effects are summarized in Table 45.2. Of most concern is its acute and chronic nephrotoxicity. Acute nephrotoxicity from CSA initially is characterized by vasoconstriction of the afferent arteriole in a dose-dependent, reversible manner. Other side effects include hyperkalemia, hypomagnesemia, hypertension, and neurotoxicity [18]. Cosmetic effects, including hirsutism and gingival hyperplasia, are also observed with the use of CSA.

With the success of CSA, researchers studied soil samples from around the world, looking for another compound that might turn out to display immunosuppressive properties. Tacrolimus (TAC), previously known as FK-506, was isolated from a soil sample in Japan in 1984 and produced by the fungus Streptomyces tsukubaensis [19]. Its effect on the lymphocyte is remarkably similar to CSA even though TAC has a completely different chemical structure. TAC acts by binding to FK-binding protein 12(FKBP12) causing inhibition of IL-2 production. The FKP12-TAC complex is 10–100 times more potent than CSA, possibly due to greater affinity for its binding protein [20]. TCA was approved by the FDA in 1994 for the use in liver transplantation. This has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants, making this drug the backbone of immunosuppressive regimens. TAC can be given intravenously, orally, or sublingually to maintain trough levels of 8–12 ng/mL for the first 3 months posttransplant; then it can be tapered to 6–10 ng/mL.

TAC metabolism is similar to CSA, via the cytochrome P450 34A system. Drug interactions are summarized in Table 45.2. Side effects include alopecia, nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and new-onset diabetes posttransplant [21].

Sirolimus (SRL) belongs to a class of compounds known as the mammalian target of rapamycin (mTOR) inhibitors. It is produced by Streptomyces hygroscopicus, a fungus isolated from a soil sample found on Easter Island. SRL, formerly known as rapamycin, was approved in 1999 by the FDA. A derivative of sirolimus, everolimus, was approved by the FDA in 2004. In response to proliferation signals provided by cytokines like IL-2, mTOR, a key regulatory kinase, changes cells from the G1 to S phase in the cell cycle [22]. The mTOR inhibitors bind to FKBP12 (same binding protein as TAC) and this complex causes inhibition of mTOR preventing the cell cycle progression from G1 to S in lymphocytes. The primary pathway for metabolism is the cytochrome P450 34A enzyme system. SRL has been used in a variety of combinations for maintenance of immunosuppression, to help withdraw, or completely avoid, the use of steroids and also as an alternative in calcineurin-sparing protocols. Drug interactions are summarized in Table 45.2. Hypertriglyceridemia is one of the most significant side effects; impaired wound healing, thrombocytopenia, leukopenia, and anemia are also associated with SRL [23, 24].

Azathioprine (AZA), a prodrug of 6-mercaptopurine, was developed in the early 1960s and was part of the first successful transplant series. AZA inhibits the purine synthesis in the de novo pathway. Purine inhibition leads to inhibition of the mixed lymphocyte reaction, and to a lesser extent, the antigen antibody reaction [25]. The use of AZA has decreased significantly with the development of new agents such as mycophenolate mofetil (MMF). However, AZA is still preferred in recipients who are considering conceiving a child, because of the teratogenic effects of MMF. The most common side effect is myelosuppression due to suppression of purine synthesis. Most patients can tolerate this effect by reducing the daily dosage, although some need to discontinue the drug entirely. Other significant side effects include hepatotoxicity, pancreatitis, neoplasia, anemia, and pulmonary fibrosis. Severe pancytopenia has been reported when AZA and allopurinol are used together. It is recommended that AZA doses be reduced by 75 % if allopurinol is added to the patient’s drug regimen [25, 26].

MMF was approved by the FDA in 1995 to prevent acute rejection in kidney recipients. It has been a major addition to the immunosuppressive arsenal and has been incorporated into routine maintenance regimens after many solid organ transplants. MMF is the prodrug of mycophenolic acid (MPA), derived from Penicillium fungi. Mycophenolic acid acts as a noncompetitive inhibitor of inosine monophosphate dehydrogenase, thereby blocking de novo purine synthesis and proliferation in the T and B lymphocytes [13]. MFF is available in capsules; the oral bioavailability approaches 100 %. MPA is glucuronidated in the liver to inactive metabolic mycophenolic acid glucuronide. The most commons side effects of MMF are GI in nature; these include nausea, vomiting, diarrhea, abdominal pain, and gastroesophageal reflux. Neutropenia and thrombocytopenia can also occur with MMF, requiring a dosage reduction. Since MMF is not metabolized by the cytochrome P450 system, interactions only affect its absorption, enterohepatic cycling, or renal excretion [27].

ATGAM is a purified gamma globulin obtained by immunizing horses with human thymocytes. Infusion into a peripheral vein is often associated with thrombophlebitis; thus, infusion into a central vein is recommended. Side effects, which are more likely related to the release of pyrogenic cytokines, include fever, chills, arthralgia, thrombocytopenia, leukopenia, and serum-like sickness [29]. To avoid the cytokine release syndrome, recipients should be premedicated with methylprednisolone (MP) and diphenhydramine hydrochloride.

Thymoglobulin is obtained by immunizing rabbits with human thymocytes. Initial kidney transplant studies show ATG-R to be statistically superior to ATGAM in preventing and reversing acute rejection episodes [30]. Administration before reperfusion is advocated to maximize antiadhesion molecules effects. Medications should be given to prevent cytokine release syndrome. Side effects include fever, chills, arthralgias, infections, thrombocytopenia, and leukopenia [29, 31].

On binding to CD3, OKT3 mediates complement-dependent cell lysis and antibody-dependent cell cytotoxicity leading to rapid clearance of T cells from peripheral circulation [28]. Along with T cell depletion, the overall effect of OKT3 is likely to be due to interrupted T cell receptor binding and internalization, disrupted trafficking, and cytokine-mediated regulatory changes. If OKT3 is effective, the percentage of CD3-positive cells in the circulation should fall to, and stay below, 5 %. Side effects may occur when cytokines (e.g., TNF, IL-2, and interferon) are released by T cells into the circulation. Premedication with MP and diphenhydramine hydrochloride is important to minimize these side effects. The most serious side effect with OKT3 is a rapidly developing, noncardiogenic pulmonary edema that can be life threatening [32]. Other side effects include neurotoxicity, nephrotoxicity, and allograft thrombosis.

Basiliximab is an anti-CD25 monoclonal antibody. The alpha subunit of the IL-2 receptor, also known as Tac or CD25, is found exclusively on activated T cells. Binding of these agents to the IL-2 receptor results in blockade of IL-2-mediated responses. Because major portions of these agents are of human origin, they tend to have much longer half-lives than does OKT3. No lymphocyte depletion occurs with basiliximab; it is not designed to treat acute rejection. Its selectivity in blocking IL-2-mediated responses makes it a powerful induction agent without the added risks of infections, malignancies, or other major side effects [33, 34].

Alemtuzumab is a CD52-specific humanized monoclonal antibody, initially used to treat chronic lymphocytic leukemia. It rapidly depletes CD52 expressing lymphocytes centrally and peripherally resulting from bulk T cell depletion with lesser depletion of B cells and monocytes. Alemtuzumab facilitates reduced maintenance immunosuppression requirements without an increase in infections or malignant complications in solid organ transplantations as compared to historical controls. Alemtuzumab causes a significant cytokine release reaction and often requires premedication [35, 36].

Rituximab is a chimeric monoclonal antibody specific for CD20, a cell surface glycoprotein involved in B cell activation and maturation [37]. It is FDA approved for treating lymphoma; however, its use has grown to include the treatment of antibody-mediated rejection and use in desensitization protocols with plasmapheresis and/or intravenous immunoglobulin [38]. The most important indication of Rituximab in solid organ transplantation is as a primary treatment of PTLD.

Eculizumab is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor, with high affinity for C5, and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). It blocks the activation of terminal complement. Adverse effects include an increased risk of infections, especially from encapsulated bacteria.

Bortezomib is a proteasome inhibitor, FDA approved for treating myeloma. It has been shown to cause apoptosis of normal plasma cells, thereby decreasing alloantibody production in sensitized patients. Several case reports and series have described the use of Bortezomib for the treatment of antibody-mediated rejection and in desensitization protocols [38–40].

Costimulatory molecules alter the threshold for activation of naive T lymphocytes without having a primary activating or inhibitory function. The two costimulatory receptors on T cells are CD28 and CD152; these serve reciprocal roles: CD28 facilitates a T cell response, whereas CD152 reduces it.

Belatacept (also known as LEA29Y) is a second-generation costimulation-blockade agent that has two amino acid substitutions. It is a high-avidity molecule with slower dissociation rates. Belatacept is a promising, nonnephrotoxic option in kidney transplant recipients and is being developed with the aim of providing calcineurin inhibitors avoidance [41, 42].

Janus kinase 3 (JAK3) is essential for the signal transduction from the cytokine receptors of several cytokines to the nucleus. JAK3 is expressed on immune cells only, making it an important target for developing new immunosuppressants. CP-690559 is the most potent and selective JAK3 inhibitor. Its effects include reduction in natural killer cell and T cell numbers, with unchanged numbers of CD8+ effector memory T cells [45].

Steroids have been a part of transplantation since its inception. It soon became clear, however, that the toxicities of steroids could overshadow their benefits. Despite numerous attempts to limit or discontinue their use, they remain an integral component of most immunosuppressive protocols. Steroids inhibit T cell proliferation, T cell-dependent immunity, and the expression of various cytokines, especially IL-2, IL-6, and interferon-γ, and tumor necrosis factor-α (TNF-α). They also suppress antibody formation and the delayed hypersensitivity response found in allograft rejection. Steroids use is associated with a series of problems, including acne, increased appetite, mood changes, diabetes, hypertension, and impaired wound healing [46]. Many transplant centers are switching to steroid-withdrawal/steroid-free protocols for many of their recipients [47, 48].