Immunosuppressive Drugs


Immunosuppressive drugs are used for the prevention or treatment of rejection after transplantation of solid organs, tissues and cells, as well as therapy of autoimmune and a variety of other diseases. Primary goals of immunosuppression are: (1) to effectively control immune responses against foreign antigens and (2) to minimise any undesired drug side effects and toxicities. The development of numerous substances, together with the understanding of their molecular action has paved the way to meet these goals, and to individualise immunosuppression. The objective of this inventory is to give a systematic overview on immunosuppressive agents currently in use or under evaluation for transplantation, as a guide for scientific research and clinical practice.

Key Concepts:

  • Immunosuppressive drugs are required for prophylaxis and therapy of rejection in solid organ transplantation.

  • A broad spectrum of immunosuppressive drugs is available and new drugs are in the pipeline or under development.

  • Some immunosuppressive drugs are critical dose drugs with a narrow therapeutic index and require therapeutic drug monitoring.

  • Calcineurin inhibitors are commonly used as the basic immunosuppressives despite their nephrotoxic potential.

  • Immunosuppressive drug combinations with different mode of actions are helpful to lower single drug dosages and avoid drug‐related adverse effects as well as to use synergistic or additive immunosuppressive effects.

  • Many factors (e.g. age, gender, liver or renal dysfunction, genetic polymorphism, drug–drug interactions, etc.) can alter the pharmacokinetics of immunosuppressive drugs.

  • Withdrawal of immunosuppressive medication in solid organ transplantation can cause graft failure.

Keywords: corticosteroids; cyclosporine A; tacrolimus; rapamycin; mycophenolate mofetil; azathioprine; monoclonal antibodies; polyclonal antibodies; new immunosuppressive drugs

Figure 1.

Interaction of graft (red) and recipient (blue) cells and tissue, for example, in kidney transplantation. The recognition of foreign antigen (afferent phase) activates a T‐cell response, which results in a specific immune response against the foreign antigen (efferent phase). The specific immune reaction from the recipient directed against the graft is called host‐versus‐graft reaction, whereas the attack against the recipient driven by the graft is a graft‐versus‐host reaction.

Figure 2.

Interaction of antigen‐presenting cell (APC) and T cell. The APC presents antigen (Ag) by major histocompatibility complex (MHC) class I or II molecules to the T cells. Antigen presented by MHC class I molecules is recognised by CD8+ T cells, and MHC class II presented antigen by CD4+ T cells. Co‐stimulatory signals are required to activate the T cells (B7–CD28, CD40–CD40L). Adhesion molecules are necessary to reinforce the intercellular contact.

Figure 3.

Intracellular T‐cell signalling. Three signals are involved in T‐cell activation. The ‘first signal’ is the interaction of MHC/Ag–TCR/CD3. The conformational alteration of the TCR/CD3 complex activates a series of protein tyrosine kinases (PTKs). The PTKs activate the calcineurin pathway. The soluble mediator inositol 1,4,5‐triphosphate (IP3) includes calcium release from the endoplasmic reticulum and through cell membrane channels. Calcium binds calmodulin and calcineurin. The activated calcineurin dephosphorylates NFATp, enabling it to translocate into the nucleus and binds it to cytokine promoters (e.g. IL‐2). The ‘second signal’ is believed to be transmitted by phosphatidyl inositol 3 OH‐kinase (PI3K) after activation of the co‐stimulatory receptor CD28. Cytokine production is initiated when ‘first signal’ and ‘second signal’ are simultaneously present. Absence of the co‐stimulatory signal results in anergy. Cytokines such as IL‐2 engage their receptors (third signal) and activate PTKs and consecutively TOR. Finally, two cyclin/CDK enzyme complexes that are essential for progression from G1‐ to S‐phase of DNA synthesis are activated in the nucleus. (Reproduced from Halloran, .)

Figure 4.

Targets of immunosuppressive drugs during T‐cell activation (steps 1–5). The immunosuppressive drugs are depicted according to their targets in the T‐cell activation process (see Inventory for abbreviations of drug names). The cell cycle phase is outlined additionally.



Adawi A, Zhang Y, Baggs R, Finkelstein J and Phipps RP (1998) Disruption of the CD40‐CD40 ligand system prevents an oxygen‐induced respiratory distress syndrome. American Journal of Pathology 152: 651–657.

Amada N, Okazaki H, Sato T, Miura S and Ohashi Y (2003) Prophylactic deoxyspergualin treatment in living‐related renal‐transplant recipients transfused with donor‐specific blood. Transplantation 75: 60–66.

Armstrong VW, Shipkova M, von Ahsen N and Oellerich M (2004) Analytic aspects of monitoring therapy with thiopurine medications. Therapeutic Drug Monitoring 26: 220–226.

Bashir SJ and Maibach HI (2001) Alefacept (Biogen). Current Opinion in Investigational Drugs 2: 631–634.

Baumgart DC, Targan SR, Dignass AU et al. (2010) Prospective randomized open‐label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid‐refractory ulcerative colitis. Inflammatory Bowel Disease 16: 620–629.

Becker YT, Becker BN, Pirsch JD and Sollinger HW (2004) Rituximab as treatment for refractory kidney transplant rejection. American Journal of Transplantation 4: 996–1001.

Behrend M and Braun F (2005) Enteric‐coated mycophenolate sodium: tolerability profile compared with mycophenolate mofetil. Drugs 65: 1037–1050.

Bhat S and Czuczman MS (2010) Galiximab: a review. Expert Opinion on Biological Therapy 10: 451–458.

Birsan T, Dambrin C, Klupp J et al. (2003) In vivo pharmacokinetic and pharmacodynamic evaluation of the malononitrilamide FK778 in non‐human primates. Transplant International 16: 354–360.

Birsan T, Dambrin C, Marsh KC et al. (2004) Preliminary in vivo pharmacokinetic and pharmacodynamic evaluation of a novel calcineurin‐independent inhibitor of NFAT. Transplant International 17: 145–150.

Boumpas DT, Furie R, Manzi S et al. (2003) A short course of BG9588 (anti‐CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis & Rheumatism 48: 719–727.

Bourdage JS and Hamlin DM (1995) Comparative polyclonal antithymocyte globulin and antilymphocyte/antilymphoblast globulin anti‐CD antigen analysis by flow cytometry. Transplantation 59: 1194–1200.

Brinkmann V, Billich A, Baumruker T et al. (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nature Review of Drug Discovery 9: 883–897.

Brochstein JA, Grupp S, Yang H, Pillemer SR and Geba GP (2010) Phase‐1 study of siplizumab in the treatment of pediatric patients with at least grade II newly diagnosed acute graft‐versus‐host disease. Pediatric Transplantation 14: 233–241.

Budde K, Sommerer C, Becker T et al. (2010) Sotrastaurin, a novel small molecule inhibiting protein kinase C: first clinical results in renal‐transplant recipients. American Journal of Transplantation 10: 571–581.

Budde K, Durr M, Liefeldt L, Neumayer HH and Glander P (2010) Enteric‐coated mycophenolate sodium. Expert Opinion on Drug Safety 9: 981–994.

Changelian PS, Flanagan ME, Ball DJ et al. (2003) Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302: 875–878.

Chapman TM and Keating GM (2003) Basiliximab: a review of its use as induction therapy in renal transplantation. Drugs 63: 2803–2835.

Chapman TM and Perry CM (2004) Everolimus. Drugs 64: 861–872.

Chen G, Luke PP, Yang H et al. (2007) Anti‐CD45RB monoclonal antibody prolongs renal allograft survival in cynomolgus monkeys. American Journal of Transplantation 7: 27–37.

Ciancio G and Burke GW III (2008) Alemtuzumab (Campath‐1H) in kidney transplantation. American Journal of Transplantation 8: 15–20.

Cooper JE and Wiseman AC (2010) Novel immunosuppressive agents in kidney transplantation. Clinical Nephrology 73: 333–343.

Denton MD, Magee CC and Sayegh MH (1999) Immunosuppressive strategies in transplantation. Lancet 353: 1083–1091.

Dubois EA and Cohen AF (2009) Abatacept. British Journal of Clinical Pharmacology 68: 480–481.

Dumont FJ (2002) IDEC‐131. IDEC/Eisai. Current Opinion in Investigational Drugs 3: 725–734.

Durrbach A, Pestana JM, Pearson T et al. (2010) A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT‐EXT study). American Journal of Transplantation 10: 547–557.

Elices MJ (2001) Tresperimus (Laboratoires Fournier). Current Opinion in Investigational Drugs 2: 372–374.

Elices MJ (2003) Natalizumab Elan/Biogen. Current Opinion in Investigational Drugs 4: 1354–1362.

Ferrant JL, Benjamin CD, Cutler AH et al. (2004) The contribution of Fc effector mechanisms in the efficacy of anti‐CD154 immunotherapy depends on the nature of the immune challenge. International Immunology 16: 1583–1594.

Frampton JE and Wagstaff AJ (2003) Alemtuzumab. Drugs 63: 1229–1243.

Fulton B and Markham A (1996) Mycophenolate mofetiln. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in renal transplantation. Drugs 51: 278–298.

Gloor JM, DeGoey SR, Pineda AA et al. (2003) Overcoming a positive crossmatch in living‐donor kidney transplantation. American Journal of Transplantation 3: 1017–1023.

Guasch A, Roy‐Chaudhury P, Woodle ES et al. (2010) Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy. Transplantation 90: 891–897.

van Gurp EA, Schoordijk‐Verschoor W, Klepper M et al. (2009) The effect of the JAK inhibitor CP‐690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation 87: 79–86.

Halloran PF (1997) Immunosuppressive agents in clinical trials in transplantation. The American Journal of the Medical Sciences 313(5): 283–288.

Heffernan MP and Leonardi CL (2010) Alefacept for psoriasis. Seminars in Cutaneous Medicine and Surgery 29: 53–55.

Henn V, Steinbach S, Buchner K, Presek P and Kroczek RA (2001) The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 98: 1047–1054.

Hourmant M, Bedrossian J, Durand D et al. (1996) A randomized multicenter trial comparing leukocyte function‐associated antigen‐1 monoclonal antibody with rabbit antithymocyte globulin as induction treatment in first kidney transplantations. Transplantation 62: 1565–1570.

Holtmann MM (2003) RDP‐58 (SangStat Medical). IDrugs 6: 1188–1194.

Inolimomab (1999) Anti‐CD25 monoclonal antibody B‐B10, anti‐interleukin‐2 receptor monoclonal antibody B‐B10, B‐B10, BT 563, Leukotac. Drugs R&D 1: 81–84.

Johnston O, Jaswal D, Gill JS et al. (2010) Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation 89: 1057–1070.

Joshi AS, King SY, Zajac BA et al. (1997) Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients. Journal of Clinical Pharmacology 37: 1121–1128.

Kaplan MJ (2001) Leflunomide Aventis Pharma. Current Opinion in Investigational Drugs 2: 222–230.

Kirk AD (2003) CDP 571: anti‐TNF monoclonal antibody, BAY 103356, BAY W 3356, Humicade. Drugs R&D 4: 174–178.

Knoll GA and Bell RC (1999) Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta‐analysis of randomised trials. British Medical Journal 318: 1104–1107.

Kobayashi K, Nakashima A, Nagata H et al. (2001) Anti‐arthritic effects of KF20444, a new immunosuppressive compound inhibiting dihydroorotate dehydrogenase, on rat collagen‐induced arthritis. Inflammation Research 50: 24–31.

Kovarik JM and Slade A (2010) Overview of sotrastaurin clinical pharmacokinetics. Therapeutic Drug Monitoring 32: 540–543.

Kuramoto T, Daikoku T, Yoshida Y et al. (2010) Novel anticytomegalovirus activity of immunosuppressant mizoribine and its synergism with ganciclovir. Journal of Pharmacology and Experimental Therapeutics 333: 816–821.

Lee J (2010) Novel combinational treatment of cisplatin with cyclophilin A inhibitors in human heptocellular carcinomas. Archives of Pharmacal Research 33: 1401–1409.

Lerut J, Van Thuyne V, Mathijs J et al. (2005) Anti‐CD2 monoclonal antibody and tacrolimus in adult liver transplantation. Transplantation 80: 1186–1193.

Lin TS, Stock W, Xu H et al. (2009) A phase I/II dose escalation study of apolizumab (Hu1D10) using a stepped‐up dosing schedule in patients with chronic lymphocytic leukemia and acute leukemia. Leukemia & Lymphoma 50: 1958–1963.

Mancini S, Amorotti E, Vecchio S, Ponz dL and Roncucci L (2010) Infliximab‐related hepatitis: discussion of a case and review of the literature. Internal and Emergency Medicine 5: 193–200.

Mathew TH (1998) A blinded, long‐term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental mycophenolate mofetil renal transplantation study group. Transplantation 65: 1450–1454.

Matthews JB, Ramos E and Bluestone JA (2003) Clinical trials of transplant tolerance: slow but steady progress. American Journal of Transplantation 3: 794–803.

Michallet MC, Preville X, Flacher M et al. (2003) Functional antibodies to leukocyte adhesion molecules in antithymocyte globulins. Transplantation 75: 657–662.

Nahar IK, Shojania K, Marra CA, Alamgir AH and Anis AH (2003) Infliximab treatment of rheumatoid arthritis and Crohn's disease. Annals of Pharmacotherapy 37: 1256–1265.

Nashan B (2005) Antibody induction therapy in renal transplant patients receiving calcineurin‐inhibitor immunosuppressive regimens: a comparative review. BioDrugs 19: 39–46.

Nicolls MR and Gill RG (2006) LFA‐1 (CD11a) as a therapeutic target. American Journal of Transplantation 6: 27–36.

Nizet Y, Chentoufi AA, de la Parra B et al. (2000) The experimental (in vitro) and clinical (in vivo) immunosuppressive effects of a rat IgG2b anti‐human CD2 mAb, LO‐CD2a/BTI‐322. Transplantation 69: 1420–1428.

Onrust SV, Lamb HM and Balfour JA (1999) Rituximab. Drugs 58: 79–88.

Opelz G and Dohler B (2004) Lymphomas after solid organ transplantation: a collaborative transplant study report. American Journal of Transplantation 4: 222–230.

Orjuela M, Gross TG, Cheung YK et al. (2003) A pilot study of chemoimmunotherapy (cyclophosphamide, prednisone, and rituximab) in patients with post‐transplant lymphoproliferative disorder following solid organ transplantation. Clinical Cancer Research 9: 3945S–3952S.

Ozkaynak E, Gao W, Shemmeri N et al. (2001) Importance of ICOS‐B7RP‐1 costimulation in acute and chronic allograft rejection. Nature Immunology 2: 591–596.

Papp K, Bissonnette R, Rosoph L et al. (2008) Efficacy of ISA247 in plaque psoriasis: a randomised, multicentre, double‐blind, placebo‐controlled phase III study. Lancet 371: 1337–1342.

Patel VL, Schwartz J and Bussel JB (2008) The effect of anti‐CD40 ligand in immune thrombocytopenic purpura. British Journal of Haematology 141: 545–548.

Pescovitz MD (2004) The use of rituximab, anti‐CD20 monoclonal antibody, in pediatric transplantation. Pediatric Transplantation 8: 9–21.

Pescovitz MD, Greenbaum CJ, Krause‐Steinrauf H et al. (2009) Rituximab, B‐lymphocyte depletion, and preservation of beta‐cell function. New England Journal of Medicine 361: 2143–2152.

Pollard S, Nashan B, Johnston A et al. (2003) A pharmacokinetic and clinical review of the potential clinical impact of using different formulations of cyclosporin A. Berlin, Germany, November 19, 2001. Clinical Therapy 25: 1654–1669.

Qi Z, Simanaitis M and Ekberg H (1999) Malononitrilamides and tacrolimus additively prevent acute rejection in rat cardiac allografts. Transplant Immunology 7: 169–175.

Renders L and Valerius T (2003) Engineered CD3 antibodies for immunosuppression. Clinical & Experimental Immunology 133: 307–309.

Riese RJ, Krishnaswami S and Kremer J (2010) Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Practice & Research Clinical Rheumatology 24: 513–526.

Salmela K, Wramner L, Ekberg H et al. (1999) A randomized multicenter trial of the anti‐ICAM‐1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European anti‐ICAM‐1 renal transplant study group. Transplantation 67: 729–736.

Schnitzbauer AA, Zuelke C, Graeb C et al. (2010) A prospective randomised, open‐labeled, trial comparing sirolimus‐containing versus mTOR‐inhibitor‐free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 10: 190.

Schuler W, Bigaud M, Brinkmann V et al. (2004) Efficacy and safety of ABI793, a novel human anti‐human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation. Transplantation 77: 717–726.

Scott LJ, McKeage K, Keam SJ and Plosker GL (2003) Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 63: 1247–1297.

Sehgal SN (2003) Sirolimus: its discovery, biological properties, and mechanism of action. Transplantation Proceedings 35: 7S–14S.

Stotler CJ, Eghtesad B, His E and Silver B (2009) Rapid resolution of GVHD after orthotopic liver transplantation in a patient treated with alefacept. Blood 113: 5365–5366.

Tredget EB, Arefanian H, Gill RG, Rajotte RV and Rayat GR (2008) Monotherapy with anti‐LFA‐1 monoclonal antibody promotes long‐term survival of rat islet xenografts. Cell Transplantation 17: 599–608.

Tuttolomondo A, Di Sciacca R, Di Raimondo D et al. (2009) Inflammation as a therapeutic target in acute ischemic stroke treatment. Current Topics in Medicinal Chemistry 9: 1240–1260.

Vincenti F (2002) What's in the pipeline? New immunosuppressive drugs in transplantation. American Journal of Transplantation 2: 898–903.

Vincenti F, Mendez R, Pescovitz M et al. (2007) A phase I/II randomized open‐label multicenter trial of efalizumab, a humanized anti‐CD11a, anti‐LFA‐1 in renal transplantation. American Journal of Transplantation 7: 1770–1777.

Vincenti F and Kirk AD (2008) What's next in the pipeline. American Journal of Transplantation 8: 1972–1981.

Weaver TA, Charafeddine AH, Agarwa A et al. (2009) Alefacept promotes co‐stimulation blockade based allograft survival in nonhuman primates. Nature Medicine 15: 746–749.

Webster AC, Ruster LP, McGee R et al. (2010) Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database of Systematic Reviews CD003897.

Williams JW, Mital D, Chong A et al. (2002) Experiences with leflunomide in solid organ transplantation. Transplantation 73: 358–366.

Yabu JM and Vincenti F (2007) Novel immunosuppression: small molecules and biologics. Seminars in Nephrology 27: 479–486.

Yang H, Chen G, Kanai N et al. (2003) Monotherapy with LF 15‐0195, an analogue of 15‐deoxyspergualin, significantly prolongs renal allograft survival in monkeys. Transplantation 75: 1166–1171.

Further Reading

(1997) Murine OKT4A immunosuppression in cadaver donor renal allograft recipients: a cooperative clinical trials in transplantation pilot study. Transplantation 63: 1087–1095.

(2004) Natalizumab: AN 100226, anti‐4alpha integrin monoclonal antibody. Drugs in R&D 5: 102–107.

Bock HA, Gallati H, Zurcher RM et al. (1995) A randomized prospective trial of prophylactic immunosuppression with ATG‐fresenius versus OKT3 after renal transplantation. Transplantation 59(6): 830–840.

Budde K, Glander P, Diekmann F et al. (2004) Review of the immunosuppressant enteric‐coated mycophenolate sodium. Expert Opin Pharmacother 5(6): 1333–1345.

De Serres SA, Sayegh MH and Najafian N (2009) Immunosuppressive drugs and Tregs: a critical evaluation!. Clinical Journal of the American Society of Nephrology 4: 1661–1669.

Dell‐Olio D and Kelly DA (2010) Immunosuppressants: what's new? Current Opinion in Organ Transplantation 15: 594–600.

Durrbach A, Francois H, Jacquet A, Beaudreuil S and Charpentier B (2010) Co‐signals in organ transplantation. Current Opinion in Organ Transplantation 15: 474–480.

Isotechnika announces phase I clinical trial results promising for small molecule anti‐rejection drug. 2006.

Marcen R (2009) Immunosuppressive drugs in kidney transplantation: impact on patient survival, and incidence of cardiovascular disease, malignancy and infection. Drugs 69: 2227–2243.

Sanchez‐Fueyo A and Strom TB (2011) Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs. Gastroenterology 140: 51–64.

Selzner N, Grant DR, Shalev I and Levy GA (2010) The immunosuppressive pipeline: meeting unmet needs in liver transplantation. Liver Transplantation 16: 1359–1372.

Snanoudj R, Zuber J and Legendre C (2010) Co‐stimulation blockade as a new strategy in kidney transplantation: benefits and limits. Drugs 70: 2121–2131.

Staatz CE, Goodman LK and Tett SE (2010) Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part I. Clinical Pharmacokinetics 49: 141–175.

Staatz CE, Goodman LK and Tett SE (2010) Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: part II. Clinical Pharmacokinetics 49: 207–221.

Wieland E, Olbricht CJ, Süsal C et al. (2010) Biomarkers as a tool for management of immunosuppression in transplant patients. Therapeutic Drug Monitoring 32: 560–572.

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Braun, Felix, Becker, Thomas, Renders, Lutz, and Ringe, Burckhardt(Jul 2012) Immunosuppressive Drugs. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001243.pub3]