You are in: eMedicine Specialties > Pediatrics: Surgery > Transplantation ImmunosuppressionArticle Last Updated: Jun 13, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 7
  Author: Randy P Prescilla, MD, Instructor in Anesthesia, Harvard Medical School; Assistant in Perioperative Anesthesia, Children's Hospital Boston Editors: Richard G Ohye, MD, Director, Pediatric Cardiac Transplantation, Fellowship Program Director, Pediatric Cardiac Surgery, Assistant Professor, Department of Surgery, Section of Cardiac Surgery, University of Michigan Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steve Dunn, MD, Chief, Solid Organ Transplantation, Department of Surgery, Alfred I DuPont Hospital for Children at Wilmington; Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center; Mary C Mancini, MD, PhD, Director of Cardiothoracic Transplantation, Professor, Department of Surgery, Louisiana State University Health Sciences Center Author and Editor Disclosure Synonyms and related keywords: immunosuppression, immunosuppressive therapy, organ transplantation, graft rejection INTRODUCTIONSection 2 of 7
  Organ transplantation elicits a complex series of immunologic processes. These processes are generally categorized as inflammation, immunity, and tissue repair and structural reinforcement of damaged tissues. Inflammation in the transplantation site is mediated by macrophages and T cells and proinflammatory mediators (eg, interleukin 2 [IL-2]). Activation of biochemical cascades (eg, classic complement cascade) results in elaboration of bioactive intermediates such as C3a and C5a. After antigens have been effectively controlled by the immune system, macrophages, endothelial cells, smooth muscle cells, and fibroblasts begin to promote repair and structural reinforcement of damaged cells. Rejection results when a pathologic and intense inflammatory response develops or when repair and remodeling of tissues fails. In hyperacute rejection, transplant patients are serologically presensitized to alloantigens (ie, graft antigens are recognized as foreign). Hyperacute rejection may develop within minutes to hours of graft implantation. In acute rejection, graft alloantigens are encountered by T cells, with resulting cytokine (and possibly antibody) release that then leads to tissue distortion, vascular insufficiency, and cell destruction. These processes can occur within 24 hours after graft implantation and continue over a period of days to weeks. In chronic rejection, pathologic tissue remodeling and reinforcement occurs. Blood flow is reduced, which leads to regional tissue ischemia, fibrosis, and cell death. The introduction of routine pretransplant screening of graft recipients for antidonor antibodies has made hyperacute rejection rare nowadays. No accepted therapeutic strategy currently exists to treat chronic rejection. The control of acute rejection has been the primary aim of immunosuppression, thereby allowing tissue repair to progress. The use of combination immunosuppressive therapy has evolved over a number of years. HISTORY OF IMMUNOSUPPRESSIONSection 3 of 7
In 1949, cortisone was shown to alleviate rheumatoid arthritis. Since then, corticosteroids have been used to treat autoimmune disorders and to prevent allograft rejection. Rhen and Cidlowski recently published a review of the anti-inflammatory action of glucocorticoids. In 1959, cyclophosphamide was demonstrated to suppress the formation of antibodies and was used for bone marrow transplantation. In the same year, 6-mercaptopurine (6-MP) was reported to suppress the immune response in rabbits. In the 1960s, azathioprine (AZA) was found to delay organ graft rejection and was used to suppress rejection of transplanted kidneys. In 1969, methotrexate was shown to inhibit antibody formation and the development of delayed hypersensitivity in guinea pigs. The T cell–inhibiting properties of cyclosporin were discovered in 1976. Cyclosporin was added to the steroid/AZA combination to prevent rejection in allograft transplants. Development of mycophenolate mofetil (MMF), an inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, began in 1982, and research continues on other IMPDH inhibitors. Tacrolimus (FK506) was shown to inhibit IL-2 production and lymphocyte proliferation in 1987. Interest in the antibiotic sirolimus ([SRL] rapamycin) was renewed in the 1980s when it was shown to prevent allograft rejection. Other immunosuppressive agents and their dates of discovery include mizoribine, 1981; leflunomide, 1978; deoxyspergualin, 1981; brequinar, 1986; azodicarbonamide, 1989; vitamin D analogs such as MC1288, 1991; and bisindolylmaleimide VIII, 1999. Other agents include Minnesota antilymphocyte globulin, antithymocyte globulin (ATG) and OKT3. IL-2 antagonists (eg, daclizumab, basiliximab) have undergone clinical studies. SDZ-RAD, a derivative of sirolimus, is also being studied. Nonpharmacologic interventions have included total body irradiation. MECHANISMS OF ACTIONSection 4 of 7
The immunosuppressive properties of older agents were discovered empirically. Most of these agents were derived from microbial products. In general, these drugs exert their effects through a limited number of mechanisms.
Immunosuppression can be achieved by several mechanisms that affect lymphocytes such as depleting lymphocytes, diverting lymphocytic traffic, or blocking lymphocyte response pathways. SMALL-MOLECULE IMMUNOSUPPRESSIVE DRUGSSection 5 of 7
Cyclosporine (Sandimmune, Neoral) Cyclosporine (CsA) was derived from the fungus Tolypocladium inflatum Gams and has been approved as a primary immunosuppressant for more than 2 decades. The complex of CsA and cyclophilin is now known to inhibit the phosphatase activity of calcineurin. By preventing calcineurin-mediated dephosphorylation, CsA inhibits translocation of the nuclear factor of activated T cells (NFAT) family of transcription factors from the cytoplasm to the nucleus of activated T cells. In addition, CsA blocks the JNK and p38 signaling pathways that are triggered by antigen recognition in T cells. Adverse effects of CsA include nephrotoxicity, systemic hypertension, gingival hyperplasia, and neurotoxicity. A possible role in promoting cancer progression and tumor cell invasion and metastasis has been raised. Mycophenolate mofetil (CellCept) and Mycophenolic acid (Myfortic) Mycophenolate mofetil (MMF) is an ester prodrug that is hydrolyzed to the active immune suppressor mycophenolic acid (MPA). MPA inhibits the activity of inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of guanosine nucleotide synthesis in B and T lymphocytes that slows their proliferative response. The unique property of MMF is its lack of cardiovascular risk and chronic nephrotoxic adverse effects. Adverse effects are primarily gastrointestinal (eg, nausea and/or vomiting, diarrhea, gastritis, duodenitis, esophagitis, ulcers). Other adverse events were related to bone marrow suppression (eg, leukopenia, anemia, thrombocytopenia). Tacrolimus (Prograf, FK506) Tacrolimus is a macrolide immunosuppressant first isolated in 1985 from Streptomyces tsukubaensis. Tacrolimus inhibits cell-mediated and humoral immune responses. Tacrolimus binds to a cytoplasmic protein FK506-binding protein 12 (FKBP12) to create a complex that inhibits phosphatase activity of calcineurin. Tacrolimus, like CsA, inhibits signal transduction pathways linked to the T-cell receptor for antigen at the level of JNK and p38 kinase. Adverse events include nephrotoxicity, neurotoxicity, and diabetogenicity, which correlate with trough levels of tacrolimus. Hypertension, hyperkalemia, and thrombotic microangiopathy have also been reported. Sirolimus (Rapamune) and Everolimus (Certican) Sirolimus (SRL) and everolimus are structurally related and engage FKBP12 to create complexes that compete for the same intracellular binding protein FKBP12. Use of SRL has improved graft survival rates and decreased rejection incidence and severity. SRL is more effective when used in combination with CsA. SRL use has also permitted CsA target-level reduction, thereby avoiding or minimizing nephrotoxicity secondary to calcineurin inhibitors. This is because the SRL-FKBP12 complex does not inhibit IL-2 production, unlike the tacrolimus-FKBP12 complex. Adverse effects include hyperlipidemia (ie, elevated cholesterol, triglycerides), leukopenia, and thrombocytopenia. FTY720 FTY720 is a synthetic small molecule that is structurally related to myricin, a sphingosine analog. FTY720 reduces the number of circulating T-cells by driving them into lymphoid tissues. Although overall toxicity is low, FTY720 can induce reversible bradycardia with the first few doses. FTY720 is undergoing phase 2 and 3 clinical trials. FK778 FK778 is undergoing phase 2 trials in kidney transplantation. A leflunomide derivative, it is derived from an inhibitor of dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis. PROTEIN IMMUNOSUPPRESSIVE DRUGSSection 6 of 7
Several proteins (polyclonal and monoclonal antibodies) have been identified to have immunosuppressive properties. Daclizumab (Zenapax) and basiliximab (Simulect) are anti-CD25 monoclonal antibodies that are widely used for induction in patients with low-to-moderate risk of rejection. There is less T-cell depletion with these agents. Moderate success and minimal toxic effects are achieved in combination with calcineurin inhibitors. Polyclonal antithymocyte globulin (Atgam, Thymoglobulin) is used as an inducing agent to produce significant lymphopenia. It is prepared by immunizing horses or rabbits (preferred) with human lymphoid cells. Toxic effects include immunodeficiency complications, thrombocytopenia, the cytokine-release syndrome, and occasional serum sickness or allergic reactions. Muromonab-CD3 (Orthoclone OKT3) is a mouse monoclonal antibody against CD3. It binds to T-cell receptor-associated CD3 complex and depletes and alters T-cells. It is used for induction and to treat rejection, although its use has declined since newer immunosuppressive drugs have reduced rejection episodes. Alemtuzumab (Campath), a humanized anti-CD52 monoclonal antibody, and rituximab (Rituxan), an anti-CD20 monoclonal antibody, are used off-label for induction and treatment of rejection, respectively. Belatacept (LEA29Y) is a second-generation cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune globulin. It combines CTLA-4 and the Fc portion of IgG. It is undergoing phase 2 trials. REFERENCESSection 7 of 7
Article Last Updated: Jun 13, 2006 |
