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Pharmacology of Immunotherapeutic Drugs pp 251–276Cite as

Transplantation: Immunologic Principles and Pharmacologic Agents

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Abstract

The transplantation of solid organs to repair or restore bodily function has always been a dream of humans since time immemorial. During the last century, the understanding of the mechanisms by which the immune system mediates organ rejection and the discovery of a wide spectrum of immunosuppressive agents has turned this ancient dream of organ replacement into a modern-day reality. Transplantation is now a routine medical procedure that is used to save lives throughout the world. In this chapter, we will discuss the immunological basis of transplantation, including solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). Furthermore, we will examine the immune mechanisms involved in transplant rejection and graft versus host disease (GVHD). This includes understanding the principles of hyperacute rejection, acute rejection, chronic rejection, and acute and chronic GVHD. The role of HLA molecules in mediating the success or failure of transplantation will be discussed extensively. In the second half of the chapter, we will explore the pharmacologic action of various immunosuppressive drugs used to maintain graft survival during SOT and prevent the development of GVHD in HSCT recipients. This will include drugs that are used in both induction and maintenance regimens, such as drugs inducing leukocyte depletion, glucocorticoids, calcineurin inhibitors, mTOR inhibitors, T cell blockers, costimulation blockers, and anti-proliferative agents. Lastly, in the bench to bedside section, we will follow the discovery and development of cyclosporine and discuss its role in initiating the modern era of successful transplantation.

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Suggested Reading

  • Almeida CC, et al. Safety of immunosuppressive drugs used as maintenance therapy in kidney transplantation: a systematic review and meta-analysis. Pharmaceuticals (Basel). 2013;6:1170–94.

    Article  CAS  Google Scholar 

  • Appelbaum FR. Hematopoietic cell transplantation as immunotherapy. Nature. 2001;411:385–9.

    Article  CAS  PubMed  Google Scholar 

  • Armitage JO. Bone marrow transplantation. N Engl J Med. 1994;330:827–38.

    Article  CAS  PubMed  Google Scholar 

  • Barker CF, Markmann JF. Historical overview of transplantation. Cold Spring Harb Perspect Med. 2013;3:a014977.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Barnett ANR, Hadjianastassiou VG, Mamode N. Rituximab in renal transplantation. Transpl Int. 2013;26:563–75.

    Article  CAS  PubMed  Google Scholar 

  • Bohmig GA, Farkas AM, Eskandary F, Wekerle T. Strategies to overcome the ABO barrier in kidney transplantation. Nat Rev Nephrol. 2015;11:732–47.

    Article  PubMed  CAS  Google Scholar 

  • Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions. 1976;6:468–75.

    Article  CAS  PubMed  Google Scholar 

  • Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. 1976. Agents Actions. 1994;43:179–86.

    Article  CAS  PubMed  Google Scholar 

  • Calne RY, White DJ, Rolles K, Smith DP, Herbertson BM. Prolonged survival of pig orthotopic heart grafts treated with cyclosporin A. Lancet. 1978;1:1183–5.

    Article  CAS  PubMed  Google Scholar 

  • Calne RY, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2:1033–6.

    Article  CAS  PubMed  Google Scholar 

  • Chang YJ, Zhao XY, Huang XJ. Strategies for enhancing and preserving anti-leukemia effects without aggravating graft-versus-host disease. Front Immunol. 2018;9:3041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi J, et al. Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients. Am J Transplant. 2017;17:2381–9.

    Article  CAS  PubMed  Google Scholar 

  • Chong AS, Alegre ML. The impact of infection and tissue damage in solid-organ transplantation. Nat Rev Immunol. 2012;12:459–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clipstone NA, Crabtree GR. Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature. 1992;357:695–7.

    Article  CAS  PubMed  Google Scholar 

  • Colombo D, Ammirati E. Cyclosporine in transplantation—a history of converging timelines. J Biol Regul Homeost Agents. 2011;25:493–504.

    CAS  PubMed  Google Scholar 

  • Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813–26.

    Article  CAS  PubMed  Google Scholar 

  • Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet. 1983;2:986–9.

    Google Scholar 

  • Dean L, National Center for Biotechnology Information (U.S.). Blood groups and red cell antigens. Bethesda: NCBI; 2005.

    Google Scholar 

  • Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Engl J Med. 2018;378:549–62.

    Article  CAS  PubMed  Google Scholar 

  • Durrbach A, Francois H, Beaudreuil S, Jacquet A, Charpentier B. Advances in immunosuppression for renal transplantation. Nat Rev Nephrol. 2010;6:160–7.

    Article  CAS  PubMed  Google Scholar 

  • Eisen HJ, et al. Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine—results at 24 months after transplantation. Transplantation. 2001;71:70–8.

    Article  CAS  PubMed  Google Scholar 

  • Enderby C, Keller CA. An overview of immunosuppression in solid organ transplantation. Am J Manag Care. 2015;21:s12–23.

    PubMed  Google Scholar 

  • Epstein FH, Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991;324:667–74.

    Article  Google Scholar 

  • Fantus D, Rogers NM, Grahammer F, Huber TB, Thomson AW. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat Rev Nephrol. 2016;12:587–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ford ML, Larsen CP. Translating costimulation blockade to the clinic: lessons learned from three pathways. Immunol Rev. 2009;229:294–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ford ML, Adams AB, Pearson TC. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nat Rev Nephrol. 2014;10:14–24.

    Article  CAS  PubMed  Google Scholar 

  • Gabardi S, Martin ST, Roberts KL, Grafals M. Induction immunosuppressive therapies in renal transplantation. Am J Health Syst Pharm. 2011;68:211–8.

    Article  CAS  PubMed  Google Scholar 

  • Ganetsky A, et al. Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract. Bone Marrow Transplant. 2019;54(2):212–7.

    Article  CAS  PubMed  Google Scholar 

  • Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med. 2004;351:2715–29.

    Article  CAS  PubMed  Google Scholar 

  • Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med. 2009;360:2645–54.

    Article  CAS  PubMed  Google Scholar 

  • Jenq RR, van den Brink MR. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer. 2010;10:213–21.

    Article  CAS  PubMed  Google Scholar 

  • Johnston JB. Mechanism of action of pentostatin and cladribine in hairy cell leukemia. Leuk Lymphoma. 2011;52:43–5.

    Article  CAS  PubMed  Google Scholar 

  • Jordan SC, Vo AA, Peng A, Toyoda M, Tyan D. Intravenous gammaglobulin (IVIG): a novel approach to improve transplant rates and outcomes in highly HLA-sensitized patients. Am J Transplant. 2006;6:459–66.

    Article  CAS  PubMed  Google Scholar 

  • Jordan SC, et al. Interleukin-6, a cytokine critical to mediation of inflammation, autoimmunity and allograft rejection. Transplantation. 2017;101:32–44.

    Article  CAS  PubMed  Google Scholar 

  • Jorgensen KA, Koefoed-Nielsen PB, Karamperis N. Calcineurin phosphatase activity and immunosuppression. A review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus. Scand J Immunol. 2003;57:93–8.

    Article  CAS  PubMed  Google Scholar 

  • Kanakry CG, Fuchs EJ, Luznik L. Modern approaches to HLA-haploidentical blood or marrow transplantation. Nat Rev Clin Oncol. 2016;13:10–24.

    Article  CAS  PubMed  Google Scholar 

  • Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–55.

    Article  CAS  PubMed  Google Scholar 

  • Klee CB, Krinks MH. Purification of cyclic 3′,5′-nucleotide phosphodiesterase inhibitory protein by affinity chromatography on activator protein coupled to Sepharose. Biochemistry. 1978;17:120–6.

    Article  CAS  PubMed  Google Scholar 

  • Kuba A, Raida L. Graft versus host disease: from basic pathogenic principles to DNA damage response and cellular senescence. Mediat Inflamm. 2018;2018:9451950.

    Article  CAS  Google Scholar 

  • Li HW, Sykes M. Emerging concepts in haematopoietic cell transplantation. Nat Rev Immunol. 2012;12:403–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991;66:807–15.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, et al. Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. Biochemistry. 1992;31:3896–901.

    Article  CAS  PubMed  Google Scholar 

  • Lutz HU. Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level. Blood. 2004;103:465–72.

    Article  CAS  PubMed  Google Scholar 

  • MacDonald KPA, Betts BC, Couriel D. Reprint of: emerging therapeutics for the control of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24:S7–S14.

    Article  PubMed  Google Scholar 

  • Malvezzi P, Jouve T, Rostaing L. Costimulation blockade in kidney transplantation. Transplantation. 2016;100:2315–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mancusi A, Piccinelli S, Velardi A, Pierini A. The effect of TNF-alpha on regulatory T cell function in graft-versus-host disease. Front Immunol. 2018;9:356.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Marcen R. Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs. 2009;69:2227–43.

    Article  CAS  PubMed  Google Scholar 

  • Mattila PS, et al. The actions of cyclosporin A and FK506 suggest a novel step in the activation of T lymphocytes. EMBO J. 1990;9:4425–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Metalidis C, Kuypers DR. Emerging immunosuppressive drugs in kidney transplantation. Curr Clin Pharmacol. 2011;6:130–6.

    Article  CAS  PubMed  Google Scholar 

  • Montgomery RA, Tatapudi VS, Leffell MS, Zachary AA. HLA in transplantation. Nat Rev Nephrol. 2018;14:558–70.

    Article  CAS  PubMed  Google Scholar 

  • Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346:580–90.

    Article  PubMed  Google Scholar 

  • Pavletic SZ, et al. Lymphodepleting effects and safety of pentostatin for nonmyeloablative allogeneic stem-cell transplantation1. Transplantation. 2003;76:877–81.

    Article  CAS  PubMed  Google Scholar 

  • Santos ESP, Bennett CL, Chakraverty R. Unraveling the mechanisms of cutaneous graft-versus-host disease. Front Immunol. 2018;9:963.

    Article  CAS  Google Scholar 

  • Scandling JD, et al. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015;15:695–704.

    Article  CAS  PubMed  Google Scholar 

  • Schrem H. Mycophenolate mofetil in liver transplantation: a review. Ann Transplant. 2013;18:685–96.

    Article  PubMed  Google Scholar 

  • Sheilagh B. Red blood cell antigens and human blood groups. In: Handbook of pediatric transfusion medicine. Elsevier; 2004. p. 45–61.

    Google Scholar 

  • Srinivas TR, Kaplan B. Transplantation in 2011: new agents, new ideas and new hope. Nat Rev Nephrol. 2011;8:74–5.

    Article  PubMed  CAS  Google Scholar 

  • Starzl TE, et al. Cyclosporin A and steroid therapy in sixty-six cadaver kidney recipients. Surg Gynecol Obstet. 1981;153:486–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med. 1994;331:365–76.

    Article  CAS  PubMed  Google Scholar 

  • Taylor AL, Watson CJE, Bradley JA. Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol. 2005;56:23–46.

    Article  PubMed  Google Scholar 

  • Ureshino H, et al. Tocilizumab for severe cytokine-release syndrome after haploidentical donor transplantation in a patient with refractory Epstein-Barr virus-positive diffuse large B-cell lymphoma. Hematol Oncol. 2017;36:324–7.

    Article  PubMed  CAS  Google Scholar 

  • van Gelder T, van Schaik RH, Hesselink DA. Pharmacogenetics and immunosuppressive drugs in solid organ transplantation. Nat Rev Nephrol. 2014;10:725–31.

    Article  CAS  PubMed  Google Scholar 

  • Wang J. CYP3A polymorphisms and immunosuppressive drugs in solid-organ transplantation. Expert Rev Mol Diagn. 2009;9:383–90.

    Article  CAS  PubMed  Google Scholar 

  • Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377:2565–79.

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Chu J, Yu J, Wei W. Cellular and molecular mechanisms in graft-versus-host disease. J Leukoc Biol. 2015;99:279–87.

    Article  PubMed  CAS  Google Scholar 

  • Zwang NA, Turka LA. Transplantation immunology in 2013: New approaches to diagnosis of rejection. Nat Rev Nephrol. 2014;10:72–4.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmaceutical and Administrative Sciences, College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, USA

    Clinton B. Mathias

  2. Pharmaceutical Science and Research, Marshall University School of Pharmacy, Huntington, WV, USA

    Jeremy P. McAleer

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  1. Clinton B. Mathias
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Correspondence to Clinton B. Mathias .

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Editors and Affiliations

  1. Department of Pharmaceutical and Administrative Sciences College of Pharmacy and Health Sciences, Western New England University, Springfield, MA, USA

    Clinton B. Mathias

  2. Pharmaceutical Science and Research School of Pharmacy, Marshall University, Huntington, WV, USA

    Jeremy P. McAleer

  3. Department of Pharmaceutical Sciences School of Pharmacy and Physician Assistant Studies, University of Saint Joseph, Hartford, CT, USA

    Doreen E. Szollosi

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Mathias, C.B., McAleer, J.P. (2020). Transplantation: Immunologic Principles and Pharmacologic Agents. In: Mathias, C., McAleer, J., Szollosi, D. (eds) Pharmacology of Immunotherapeutic Drugs. Springer, Cham. https://doi.org/10.1007/978-3-030-19922-7_8

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