Pediatric Immunosuppression
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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 to treat chronic rejection is recognized.
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.
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 have published a review of the anti-inflammatory action of glucocorticoids. [1, 2]
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. [3]
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. [4]
Tacrolimus (FK506) was shown to inhibit interleukin (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. [3]
Other immunosuppressive agents and their dates of discovery include mizoribine in 1981, leflunomide in 1978, deoxyspergualin in 1981, muromab-CD3 (OKT3) in 1985, brequinar in 1986, azodicarbonamide in 1989; vitamin D analogs such as MC1288 in 1991, and bisindolylmaleimide VIII in 1999. Other agents include Minnesota antilymphocyte globulin and antithymocyte globulin (ATG).
IL-2 antagonists (eg, basiliximab) have undergone clinical studies. SDZ-RAD, a derivative of sirolimus, is also under investigation.
Nonpharmacologic interventions have included total body irradiation.
The immunosuppressive properties of older agents were empirically discovered. Most of these agents were derived from microbial products. In general, these drugs exert their effects through a limited number of mechanisms.
Regulators of gene expression: The classic examples are glucocorticoids; others include vitamin D analogs and deoxyspergualin. Recent studies have shown that glucocorticoids affect inflammation by other (nongenomic) mechanisms.
Alkylating agents: Cyclophosphamide and other alkylate deoxyribonucleic acid (DNA) agents are mutagenic and can increase the risk of developing cancer.
Kinases and phosphatases inhibitors: These include cyclosporin A (CsA), tacrolimus (FK506), and sirolimus (SRL), which inhibit kinase cascades.
Inhibitors of de novo purine synthesis: The first-generation inhibitors are 6-mercaptopurine and azathioprine; the second-generation inhibitors are mizoribine and MMF. Potential third-generation enzymes include inhibition of inosine monophosphate dehydrogenase and inhibition of T lymphocyte–specific purine nucleoside phosphorylase. The polygentamate derivatives of methotrexate are antifolate compounds and inhibit de novo purine synthesis.
Inhibitors of de novo pyrimidine synthesis: These inhibitors include brequinar, leflunomide, and the structurally related malononitrilamides that inhibit dihydroorotate dehydrogenase.
Immunosuppression can be achieved by several mechanisms that affect lymphocytes such as depleting lymphocytes, diverting lymphocytic traffic, or blocking lymphocyte response pathways.
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.
A retrospective study of 141 kidney transplant recipients compared the results of those treated with or without CsA. The findings of the 3-month, 24-month, and 10-year protocol biopsies suggest that although histological lesions are commonly attributed to CsA nephrotoxicity, they were not specific enough to definitively diagnose calcineurin inhibitor nephrotoxicity. [5]
Tacrolimus (Prograf, Astagraf XL, Hecoria)
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.
Novel calcineurin inhibitor
Voclosporin (VCS) is a novel calcineurin inhibitor being developed for organ transplantation. The PROMISE study, a 6-month, open-label, randomized, multicenter study, found that VCS was shown to be as effective as tacrolimus with similar rates of hypertension and adverse events, and no difference was noted in mycophenolic acid exposure. VCS did show excellent correlation between trough and area under the curve and was potentially associated with a reduced incidence of new-onset diabetes after transplantation. These results suggest that VSC may be a viable alternative to tacrolimus in preventing acute rejection. [6]
Sirolimus (Rapamune) and everolimus (Zortress)
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.
One study analyzed linear growth in children who received SRL therapy after renal transplantation versus those who were maintained on tacrolimus, and whether SRL had an adverse effect on growth. Using data from 25 children aged 1-15 years, height z-scores at baseline were compared with those at 24 months. The results noted that height z-scores did not change significantly over 24 months in the SRL group; height z-scores in both groups were no different at baseline and after 24 months. These results suggest that linear growth was similar in groups and SRL did not show an adverse effect on growth. [7]
After a minimum follow-up of 6 months, data from one study noted that sirolimus was effective in rescuing pediatric patients with acute and chronic allograft rejection after liver transplantation; those with calcineurin inhibitor–induced nephropathy realized improved renal function. [8]
Data from another study noted that immunotherapy with the addition of sirolimus improved renal function in pediatric heart transplant patients with calcineurin inhibitor–induced renal insufficiency. Additionally, therapy with sirolimus and lower-dose calcineurin inhibitors can effectively prevent rejection with acceptable adverse effects. [9]
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 GI (eg, nausea and/or vomiting, diarrhea, gastritis, duodenitis, esophagitis, ulcers). Other adverse events were related to bone marrow suppression (eg, leukopenia, anemia, thrombocytopenia).
FTY720
FTY720 is the first agent in this class. S1P-R agonists reduce recirculation of lymphocytes from the lymphatic system to the blood and peripheral tissues. 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 3 clinical trials.
FK778
FK778 is a malononitrilamide (MNA) that has been demonstrated to have both immunosuppressive and anti-proliferative activities. The MNAs inhibit both T-cell and B-cell function by blocking de novo pyrimidine synthesis, through blockade of the pivotal mitochondrial enzyme dihydroorotic acid dehydrogenase (DHODH), and the inhibition of tyrosine kinase activity.
FK778 is a leflunomide derivative. It is derived from an inhibitor of dihydroorotate dehydrogenase, a key enzyme in pyrimidine synthesis. It is undergoing phase 2 trials in kidney transplantation.
Several proteins (polyclonal and monoclonal antibodies) have been identified to have immunosuppressive properties.
Antithymocyte globulin
Polyclonal antithymocyte globulin (Atgam, Thymoglobulin) is prepared from the serum of rabbits immunized with human thymocytes. Antithymocyte globulin contains cytotoxic antibodies that bind to CD2, CD3, CD4, CD8, CD11a, CD18, CD25, CD44, CD45 and HLA class I and II molecules on the surface of human T lymphocytes. The antibodies deplete circulating lymphocytes by direct cytotoxicity (both complement and cell-mediated) and block lymphocyte function by binding to cell surface molecules involved in the regulation of cell function.
Monoclonal antibodies [10]
Anti-CD3 monoclonal antibodies: 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.
Anti–interleukin (IL)-2 receptor (anti-CD25) antibodies: 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. Less T-cell depletion is observed with these agents. Moderate success and minimal toxic effects are achieved in combination with calcineurin inhibitors. [11] Daclizumab was withdrawn from the United States market because of diminished use and emergence of other effective therapies.
Anti-CD52 antibodies: Alemtuzumab (Campath-1H) is a humanized anti-CD52 monoclonal antibody that is approved for use in chronic lymphocytic leukemia. The target, CD52, is a glycoprotein expressed on lymphocytes, monocytes, macrophages, and natural killer cells. The drug causes extensive lympholysis by inducing apoptosis of targeted cells.
Anti-CD20 antibodies: Rituximab (Rituxan), an anti-CD20 monoclonal antibody, is approved for the treatment of certain types of non-Hodgkin lymphoma and to reduce the signs and symptoms of moderate to severe rheumatoid arthritis.
Anti–tumor necrosis factor (TNF) reagents
Infliximab (Remicade) is an anti-TNF alpha monoclonal antibody that binds with high affinity to TNF-alpha and prevents the cytokine from binding to its receptors. It is approved for treating the symptoms of rheumatoid arthritis, and is used in combination with methotrexate. It is also approved for the treatment of symptoms of moderate-to-severe Crohn disease.
Adalimumab (Humira) is another anti-TNF product. It is approved for use in reducing the signs and symptoms of moderate to severe rheumatoid arthritis, severe polyarticular juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and moderate to severe Crohn disease. It is also approved for the treatment of moderate to severe chronic plaque psoriasis.
LFA-1 inhibitors
Efalizumab (Raptiva) is a humanized IgG1 monoclonal antibody targeting the CD11a chain of LFA-1 (lymphocyte function associated antigen). Efalizumab binds to LFA-1 and prevent the LFA intercellular adhesion molecule interaction, which then results in blocking the T-cell adhesion, trafficking and activation.
Efalizumab, a drug indicated for psoriasis, is being withdrawn from the US market and will no longer be available after June 8, 2009, because of potential risk for progressive multifocal leukoencephalopathy (PML). PML is a rapidly progressive CNS infection caused by JC virus that leads to death or severe disability. Demyelination associated with PML is a result of the JC virus infection. JC virus belongs to the genus Polyomavirus of the Papovaviridae. PML should be considered in any patient with newly onset neurologic manifestations who has taken efalizumab. For more information, see the Food and Drug Administration MedWatch Safety Alert.
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Weaver DJ Jr, Selewski D, Janjua H, Iorember F. Improved cardiovascular risk factors in pediatric renal transplant recipients on steroid avoidance immunosuppression: A study of the Midwest Pediatric Nephrology Consortium. Pediatr Transplant. 2015 Nov 20. [Medline].
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Randy P Prescilla, MD Instructor in Anesthesia, Harvard Medical School; Assistant in Perioperative Anesthesia, Children’s Hospital Boston
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Mary C Mancini, MD, PhD, MMM Surgeon-in-Chief and Director of Cardiothoracic Surgery, Christus Highland
Mary C Mancini, MD, PhD, MMM is a member of the following medical societies: American Association for Thoracic Surgery, American College of Surgeons, American Surgical Association, Phi Beta Kappa, Society of Thoracic Surgeons
Disclosure: Nothing to disclose.
Richard G Ohye, MD Head, Section of Pediatric Cardiovascular Surgery, Associate Professor of Cardiac Surgery, Program Director, Pediatric Cardiac Surgery Fellowship, University of Michigan Medical Center
Richard G Ohye, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Thoracic Surgery, Congenital Heart Surgeons Society, Society of University Surgeons, American College of Cardiology, American College of Chest Physicians, American College of Surgeons, Association for Academic Surgery, International Society for Heart and Lung Transplantation, Society of Thoracic Surgeons
Disclosure: Nothing to disclose.
Pediatric Immunosuppression
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