TRANSPLANT IMMUNOSUPPRESSION
Immunosuppressive Agents
Immunosuppressive agents are the mainstream therapies used to overcome immunologic barriers to transplantation and to prevent allograft rejection. Immunosuppressive agents are divided into different categories depending on when they are given in relation to time of transplant ( Fig. 40-1 ).
Categories of Agents
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Induction agents
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Antibody induction
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Monoclonal antibodies: basiliximab, daclizumab, alemtuzumab, OKT3
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Polyclonal antibodies: antithymocyte globulin (rabbit), antithymocyte globulin (equine)
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Administered intravenously in the perioperative period
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Induce acute, powerful, short-lived immunosuppression
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Primary Immunosuppressant
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Calcineurin inhibitors (CNIs) are the cornerstones of immunosuppressive therapy. These drugs include tacrolimus and cyclosporine A (CsA) and can be administered by the oral, intravenous, or inhalational route.
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Adjuvant agents
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One or more medications prescribed in addition to a CNI
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Antiproliferative agents
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Azathioprine, mycophenolate mofetil, mycophenolate sodium, sirolimus, and everolimus
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Corticosteriods
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Methylprednisolone and prednisone
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Induction Agents
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Interleukin-2 (IL-2) receptor blockers
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Basiliximab (Simulect)
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Mechanism of action
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Binds to activated lymphocyte IL-2 receptor alpha chains ( Fig. 40-2 )
Figure 40-2
Mechanism of action of daclizumab and basiliximab. Daclizumab is a selective, modified human IgG1 monoclonal antibody specific for alpha subunit (CD25) of interleukin-2 receptor; inhibits interleukin-2–dependent human T-lymphocyte activation. Basiliximab is a chimeric interleukin-2 receptor antagonist. It is directed against the interleukin-2R-alpha chain (CD25) on activated T lymphocytes, and is a potent inhibitor of interleukin-2–mediated activation of lymphocytes, a critical pathway in the cellular immune response involved in allograft rejection.
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Dosing
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20 mg intravenous piggyback (IVPB) given on POD #0 and #4; total of two doses
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Diluent: normal saline only
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Chimeric (70%/30%)
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Administration time: 15 minutes
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Line access: either peripheral or central line
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Side effects
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Hypotension, hypersensitive reaction, tachycardia, bronchospasm, pulmonary edema, and infection
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Daclizumab (Zenapax)
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Mechanism of Action
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Same as basiliximab
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Dosing
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1 mg/kg (maximum 100 mg) IVPB Q14 days for total of up to five doses
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Diluent: normal saline only
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Ninety percent humanized
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Administration time: 15 minutes
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Line access: either peripheral or central line
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Side effects: same as basiliximab
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Humanized anti-CD52 monoclonal antibody
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Alemtuzumab (Campath)
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Mechanism of action
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Proposed antibody dependent lysis of lymphocytes after binding
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Unconjugated; therefore, it relies on the Ab itself to kill cells directly or through activation of complement T cells
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Causes transient but profound depletion of mature T cells and some depletion of B cells and monocytes but not bone marrow
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Dosing
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Alemtuzumab is administered one time as 30-mg subcutaneous injection (2 ×15-mg syringes) in either the buttocks or thighs.
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Premedications: methylprednisolone, acetaminophen, and diphenhydramine
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Side effects
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Anemia, neutropenia, thrombocytopenia, autoimmune hemolytic anemia (rare), infusion site reactions (rigors, fever, nausea and vomiting [N/V], rash, itching), infections
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Monitoring
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Complete blood count, absolute lymphocyte account
Anti-CD3 murine monoclonal antibody
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Muromonab CD3 (Orthoclone OKT3)
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Mechanism of action
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Reacts with T-3 antigen, recognizing structure
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Blocks T-cell effector function
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Dose:
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5 mg intravenous piggyback (IVP) in less than 1 minute for 7 to 14 days
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Premedications: methylprednisolone, acetaminophen, and diphenhydramine
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Side effects
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Flulike syndrome
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Pulmonary edema
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Aseptic meningitis
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Hypotension
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Serious infection (including cytomegalovirus, post-transplant lymphoproliferative disease)
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Seizure
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Monitoring parameters
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Fluid status: chest x-ray study, body weight (BW)
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Frequent vital signs
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First dose reactions
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Efficacy: CD3 level
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Tolerance: OKT-3 antibody
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Note: Owing to severe adverse reactions (e.g., anaphylactic and cytokine release syndrome), which may occur with any dose or course, use of OKT3 is less desirable in the current era.
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Antithymocyte globulin (ATG)
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Equine polyclonal immunoglobulin G (IgG) antibody (Atgam)
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Mechanism of action
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Reduces number and alters function of circulating T lymphocytes
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Dose
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10 to 20 mg/kg/d intravenous (IV) over 6 to 8 h for 7 to 14 days via central line
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Premedications: methylprednisolone, acetaminophen, and diphenhydramine
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Skin testing is required
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Side effects
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Fever, chills, leukopenia, pain, headache, abdominal pain, diarrhea, hypertension, nausea, and thrombocytopenia
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Monitoring parameters
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ATG/thymoglobulin protocol
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Platelets higher than 100,000 or white blood cell count (WBC) higher than 3000: Full dose
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Platelets between 50,000 and 100,000 or WBC between 2000 and 3000: Half dose
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Platelets less than 50,000 or WBC less than 2000: Hold dose
1. Rabbit polyclonal IgG antibody (thymoglo-bulin)
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Mechanism of action
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Same as equine polyclonal IgG antibody
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Dose
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1.25 to 1.5 mg/kg/d for 7 to 14 days
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Pharmacokinetic (PK) profile: t 1/2 30 days (14–45 days)
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Infusion rate: First dose over 6 to 8 hours; subsequent doses over 4 to 6 hours
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Central line preferred
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No skin testing required
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Premedications methylprednisolone, acetaminophen, and diphenhydramine
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Side effects and monitoring
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Same as equine polyclonal IgG antibody
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Summary of Antibody Therapy Prior to Anti-CD25 (IL-2 Blockers) mAbs
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Polyclonal antibodies (e.g., ATG, antilymphocyte globulin [ALG]) and monoclonal antibody (OKT3) used for reversal of acute rejection and prophylactic induction
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When used in prophylactic setting:
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Reduce incidence of early calcineurin-associated nephrotoxicity
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Decrease incidence and duration of graft dysfunction
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Delays the time of first rejection
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Antigen nonspecific, increasing the risk of over immunosuppression
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Primary Immunosuppressants
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CNIs
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CsA (Neoral)
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Mechanism of action
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CsA binds to cyclophylin. This action inhibits the antigenic response of helper T lymphocytes and suppresses the production of IL-2 and interferon-gamma. In addition, production of the receptor site for IL-2 on T lymphocytes is inhibited.
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Dose
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PO: 4 to 6 mg/kg/day, given in divided doses, every 12 hours
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IV: 1/3 of PO dose BID over 4 hours
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Target CsA levels
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First 3 months, 250 to 300 ng/mL
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3 to 6 months, 200 to 250 ng/mL
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6 to 12 months, 150 to 200 ng/mL
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More than 12 months, 100 to 150 ng/mL
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Tacrolimus (Prograf)
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Mechanism of action
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Tacrolimus binds to an intracellular protein, called FKBP-12. A complex is formed that inhibits the phosphatase activity of calcineurin. This may prevent dephosphorylation and translocation of nuclear factor of activated T cells, which is believed to initiate gene transcription for lymphokines.
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Dose
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PO: 0.1 to 0.2 mg/kg/d given in divided doses, every 12 hours
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IV: 1/3 of PO dose via continuous infusion.
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IV should be avoided unless absolutely necessary. Switch to oral or nasogastric tube feeding as soon as possible to avoid nephrotoxicity.
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Target tacrolimus levels
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First 3 months, 15 to 20 ng/mL
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3 to 6 months, 12 to 15 ng/mL
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6 months and beyond, 10-12 ng/mL
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CNI side effects ( Table 40-1 )
