Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Overview of immunosuppressive agents used for prevention and treatment of graft-versus-host disease

Nelson J Chao, MD
Section Editor
Robert S Negrin, MD
Deputy Editor
Alan G Rosmarin, MD


Graft-versus-host disease (GVHD) is the result of an intricate immune response following allogeneic stimuli. GVHD, which can be acute and/or chronic, occurs when T cells of the donor recognize the presence of histocompatibility antigens in the host that differ from those of the donor cells. This initial antigen recognition is followed by amplification of the T cell recognition process.

The proliferation of activated T cells leads to the production and secretion of a variety of cytokines, which are responsible for the inflammatory effects and tissue damage associated with GVHD [1]. Much of the damage is caused by inflammatory cytokines, such as interleukin (IL)-1, IL-2, tumor necrosis factor (TNF), and gamma-interferon [2]. Use of immunosuppressive agents such as cyclosporine, tacrolimus (FK506), and sirolimus have delineated the critical events that lead to the activation of these alloreactive T cells and the subsequent amplification of the signals involved in T cell proliferation. These laboratory studies have led to an understanding of the mechanisms of action of specific immunosuppressants. Further, such understanding allows for the development and testing of novel immunosuppressive agents.

This topic review will focus on the most commonly used commercially available immunosuppressive drugs for prevention and/or treatment of GVHD. Discussions of the pathogenesis, clinical manifestations, diagnosis, prevention, and treatment of acute and chronic GVHD are found elsewhere in the program. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Clinical manifestations, diagnosis, and grading of chronic graft-versus-host disease" and "Treatment of chronic graft-versus-host disease" and "Prevention of acute graft-versus-host disease".)


Corticosteroids — Corticosteroids are the most widely used "front-line" therapy for the treatment of clinical GVHD. Drugs of this class have been combined with other immunosuppressants in the prophylaxis against GVHD. However, we still do not fully understand their mechanism of action. This has resulted in empiricism in the development of therapeutic doses and anecdotal reports of efficacy in certain clinical settings.

Mechanism of action — The most commonly utilized corticosteroid is methylprednisolone, which differs from prednisolone and prednisone only by the addition of a 6-alpha-methyl group. The 6-alpha-methyl group blocks the specific binding of this corticosteroid to transcortin, the protein that transports steroids in the plasma. Instead, methylprednisolone is primarily bound to albumin. The frequent side effects from methylprednisolone may be dependent on the albumin level in the host.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jun 2017. | This topic last updated: Jul 20, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991; 324:667.
  2. Antin JH, Ferrara JL. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80:2964.
  3. Oosterhuis B, ten Berge IJ, Schellekens PT, et al. Prednisolone concentration-effect relations in humans and the influence of plasma hydrocortisone. J Pharmacol Exp Ther 1986; 239:919.
  4. Almawi WY, Lipman ML, Stevens AC, et al. Abrogation of glucocorticoid-mediated inhibition of T cell proliferation by the synergistic action of IL-1, IL-6, and IFN-gamma. J Immunol 1991; 146:3523.
  5. Holler E, Kolb HJ, Wilmanns W. Treatment of GVHD--TNF-antibodies and related antagonists. Bone Marrow Transplant 1993; 12 Suppl 3:S29.
  6. Chao NJ, Schmidt GM, Niland JC, et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease. N Engl J Med 1993; 329:1225.
  7. Chao NJ, Snyder DS, Jain M, et al. Equivalence of 2 effective graft-versus-host disease prophylaxis regimens: results of a prospective double-blind randomized trial. Biol Blood Marrow Transplant 2000; 6:254.
  8. Bleyer WA. Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev 1977; 4:87.
  9. Storb R, Epstein RB, Graham TC, Thomas ED. Methotrexate regimens for control of graft-versus-host disease in dogs with allogeneic marrow grafts. Transplantation 1970; 9:240.
  10. Zaharko DS, Fung WP, Yang KH. Relative biochemical aspects of low and high doses of methotrexate in mice. Cancer Res 1977; 37:1602.
  11. Bertino JR. Karnofsky memorial lecture. Ode to methotrexate. J Clin Oncol 1993; 11:5.
  12. Schilsky RL, Bailey BD, Chabner BA. Methotrexate polyglutamate synthesis by cultured human breast cancer cells. Proc Natl Acad Sci U S A 1980; 77:2919.
  13. Fabre G, Goldman ID. Formation of 7-hydroxymethotrexate polyglutamyl derivatives and their cytotoxicity in human chronic myelogenous leukemia cells, in vitro. Cancer Res 1985; 45:80.
  14. Storb R, Deeg HJ, Fisher L, et al. Cyclosporine v methotrexate for graft-v-host disease prevention in patients given marrow grafts for leukemia: long-term follow-up of three controlled trials. Blood 1988; 71:293.
  15. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314:729.
  16. Nevill TJ, Tirgan MH, Deeg HJ, et al. Influence of post-methotrexate folinic acid rescue on regimen-related toxicity and graft-versus-host disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 9:349.
  17. Borel JF. The history of cyclosporin A and its significance. In: Cyclosporin A, White DG (Ed), Elsevier, New York 1982. p.5.
  18. Bierer BE. Advances in therapeutic immunosuppression: Biology, molecular actions and clinical implications. Curr Opin Hematol 1993; 1:149.
  19. Bram RJ, Hung DT, Martin PK, et al. Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol Cell Biol 1993; 13:4760.
  20. Gething MJ, Sambrook J. Protein folding in the cell. Nature 1992; 355:33.
  21. Nebert DW, Nelson DR, Adesnik M, et al. The P450 superfamily: updated listing of all genes and recommended nomenclature for the chromosomal loci. DNA 1989; 8:1.
  22. Bennett WM, Pulliam JP. Cyclosporine nephrotoxicity. Ann Intern Med 1983; 99:851.
  23. Petric R, Freeman D, Wallace C, et al. Effect of cyclosporine on urinary prostanoid excretion, renal blood flow, and glomerulotubular function. Transplantation 1988; 45:883.
  24. Gluckman E, Lokeic F, Devergie A. Pharmacokinetic monitoring of cyclosporine in allogeneic bone marrow transplants. Transplant Proc 1980; 20:122.
  25. Santos GW, Tutschka PJ, Brookmeyer R, et al. Cyclosporine plus methylprednisolone versus cyclophosphamide plus methylprednisolone as prophylaxis for graft-versus-host disease: A randomized double-blind study in patients undergoing allogeneic marrow transplantation. Clin Transplant 1987; 1:21.
  26. Yee GC, Self SG, McGuire TR, et al. Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation. N Engl J Med 1988; 319:65.
  27. Kino T, Hatanaka H, Miyata S, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987; 40:1256.
  28. Jusko WJ, Piekoszewski W, Klintmalm GB, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57:281.
  29. Mekki Q, Lee C, Aweeka F, et al. Pharmacokinetics of tacrolimus (FK506) in kidney transplant patients. Clin Pharmacol Ther 1993; 53:238.
  30. Wong R, Beguelin GZ, de Lima M, et al. Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation. Br J Haematol 2003; 122:128.
  31. Przepiorka D, Ippoliti C, Khouri I, et al. Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation. Blood 1996; 88:4383.
  32. Fay JW, Wingard JR, Antin JH, et al. FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. Blood 1996; 87:3514.
  33. Nash RA, Etzioni R, Storb R, et al. Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. Blood 1995; 85:3746.
  34. Ratanatharathorn V, Nash RA, Przepiorka D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 1998; 92:2303.
  35. Fung J, Abu-Elmagd K, Jain A, et al. A randomized trial of primary liver transplantation under immunosuppression with FK 506 vs cyclosporine. Transplant Proc 1991; 23:2977.
  36. Lewis WD, Jenkins RL, Burke PA, et al. FK 506 rescue therapy in liver transplant recipients with drug-resistant rejection. Transplant Proc 1991; 23:2989.
  37. Armitage JM, Kormos RL, Fung J, Starzl TE. The clinical trial of FK 506 as primary and rescue immunosuppression in adult cardiac transplantation. Transplant Proc 1991; 23:3054.
  38. Sehgal SN, Baker H, Vézina C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo) 1975; 28:727.
  39. Martel RR, Klicius J, Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol 1977; 55:48.
  40. Morris RE, Meiser BM. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989; 17:609.
  41. Armand P, Gannamaneni S, Kim HT, et al. Improved survival in lymphoma patients receiving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning. J Clin Oncol 2008; 26:5767.
  42. Griffith JP, Kim JL, Kim EE, et al. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 1995; 82:507.
  43. Morice WG, Brunn GJ, Wiederrecht G, et al. Rapamycin-induced inhibition of p34cdc2 kinase activation is associated with G1/S-phase growth arrest in T lymphocytes. J Biol Chem 1993; 268:3734.
  44. Nourse J, Firpo E, Flanagan WM, et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 1994; 372:570.
  45. Altmeyer A, Dumont FJ. Rapamycin inhibits IL-1-mediated interferon-gamma production in the YAC-1 T cell lymphoma. Cytokine 1993; 5:133.
  46. Lai JH, Tan TH. CD28 signaling causes a sustained down-regulation of I kappa B alpha which can be prevented by the immunosuppressant rapamycin. J Biol Chem 1994; 269:30077.
  47. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation 2001; 72:1924.
  48. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood 2007; 109:3108.
  49. Cutler C, Logan B, Nakamura R, et al. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood 2014; 124:1372.
  50. Cutler C, Stevenson K, Kim HT, et al. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood 2008; 112:4425.
  51. Rodriguez R, Nakamura R, Palmer JM, et al. A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplantation using 3 conditioning regimens. Blood 2010; 115:1098.
  52. Franklin TJ, Cook JM. The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem J 1969; 113:515.
  53. Morris RE, Hoyt EG, Murphy MP, et al. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc 1990; 22:1659.
  54. Storb R, Yu C, Wagner JL, et al. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997; 89:3048.
  55. Hovi T, Allison AC, Allsop J. Rapid increase of phosphoribosyl pyrophosphate concentration after mitogenic stimulation of lymphocytes. FEBS Lett 1975; 55:291.
  56. Schiff MH, Goldblum R, Rees MMC. 2-Morpholino-ethyl mycophenolic acid (ME-MPA) in the treatment of refractory rheumatoid arthritis. Arthritis Rheum 1990; 33:s1.
  57. Jacobson P, Green K, Rogosheske J, et al. Highly variable mycophenolate mofetil bioavailability following nonmyeloablative hematopoietic cell transplantation. J Clin Pharmacol 2007; 47:6.
  58. Bhatia S, Ramsay NK, Steinbuch M, et al. Malignant neoplasms following bone marrow transplantation. Blood 1996; 87:3633.
  59. Arai S, Sahaf B, Narasimhan B, et al. Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 2012; 119:6145.
  60. Glass B, Hasenkamp J, Wulf G, et al. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol 2014; 15:757.
  61. Nicholson SE, Oates AC, Harpur AG, et al. Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine-phosphorylated after receptor activation. Proc Natl Acad Sci U S A 1994; 91:2985.
  62. Schwab L, Goroncy L, Palaniyandi S, et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med 2014; 20:648.
  63. Giroux M, Delisle JS, Gauthier SD, et al. SMAD3 prevents graft-versus-host disease by restraining Th1 differentiation and granulocyte-mediated tissue damage. Blood 2011; 117:1734.
  64. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013; 122:1192.
  65. He YW, Adkins B, Furse RK, Malek TR. Expression and function of the gamma c subunit of the IL-2, IL-4, and IL-7 receptors. Distinct interaction of gamma c in the IL-4 receptor. J Immunol 1995; 154:1596.
  66. Hechinger AK, Smith BA, Flynn R, et al. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD. Blood 2015; 125:570.
  67. Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123:3832.
  68. Tefferi A, Pardanani A. Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86:1188.
  69. Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med 1987; 166:1280.
  70. Shalaby MR, Fendly B, Sheehan KC, et al. Prevention of the graft-versus-host reaction in newborn mice by antibodies to tumor necrosis factor-alpha. Transplantation 1989; 47:1057.
  71. Holler E, Kolb HJ, Möller A, et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood 1990; 75:1011.
  72. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 2008; 111:2470.
  73. Wallace PM, Johnson JS, MacMaster JF, et al. CTLA4Ig treatment ameliorates the lethality of murine graft-versus-host disease across major histocompatibility complex barriers. Transplantation 1994; 58:602.
  74. Gribben JG, Guinan EC, Boussiotis VA, et al. Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool. Blood 1996; 87:4887.
  75. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, et al. Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. Blood 1995; 85:2607.
  76. Guinan EC, Boussiotis VA, Neuberg D, et al. Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med 1999; 340:1704.
  77. Vallera DA, Panoskaltsis-Mortari A, Jost C, et al. Anti-graft-versus-host disease effect of DT390-anti-CD3sFv, a single-chain Fv fusion immunotoxin specifically targeting the CD3 epsilon moiety of the T-cell receptor. Blood 1996; 88:2342.