• Juan C. Gea-Banacloche


Immunomodulation encompasses all therapeutic interventions aimed at modifying the immune response. Augmentation of the immune response is desirable to prevent infection in states of immunodeficiency, to fight established infections and to fight cancer. In immunodeficiencies, treatment of the cause is most important (e.g., malnutrition, HIV). Specific immune defects can seldom be corrected, and the establishment of a new immune system by allogeneic stem cell transplantation should be considered. To prevent infection, vaccination, is the most effective immunomodulatory technique. New tools to manipulate the response to vaccines involve the use of cytokines, viral vectors and even “naked DNA.” For the treatment of established infections, attempts to shift the immune response toward a Th1-type phenotype are desirable. For the treatment of cancer, efforts have focused mainly in making the cancer the preferred target of the immune system of the patient. To this effect, a variety of approaches have been used, including cytokines, anti-CTL-4, tumor-specific antibodies and cellular therapies using tumor infiltrating lymphocytes and even stem cell transplantation. In allergy, autoimmunity and organ transplantation the goal is to weaken the immune response. Selected allergies may be treated by specific desensitization. In autoimmunity and transplantation, drugs that blunt all immune responses are often used. A variety of drugs with different targets are used alone and in combination to induce immunosuppression. These agents interfere with antigen presentation (anti-CD 154, CTLA4-Ig), T-cell activation (calcineurin inhibitors, including cyclosporine A and tacrolimus), or T-cell proliferation (sirolimus, mycophenolate mofetil, leflunomide). Corticosteroids act at several levels of the immune response and also have significant anti-inflammatory properties. These drugs are necessary in solid organ transplantation to prevent rejection, or treat it if it ensues. When rejection proceeds despite the use of immuno-suppressive agents, the graft is lost and a new organ is required. In stem cell transplantation, the equivalent of rejection is graft vs host disease, a pathological condition where the newly acquired immune system recognizes the recipient as foreign and mounts an immune response against it. When graft vs host disease does not respond to steroids, the treatment options are very limited and the prognosis is poor.

Key Words

Allergy autoimmunity calcineurin inhibitors corticosteroids extracorporeal photopheresis graft vs host disease immunodeficiency immunomodulation lymphocytes rejection tumor infiltrating lymphocytes transplantation vaccination 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Selected References

  1. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med 1991;324(8):509–516.CrossRefGoogle Scholar
  2. Autran B, Carcelain G, Combadiere B, Debre P. Therapeutic vaccines for chronic infections. Science 2004;305(5681):205–208.Google Scholar
  3. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 1998;339(17): 1186–1193.Google Scholar
  4. Bacigalupo A, Van Lint MT, Frassoni F, Marniont A. Graft-versusleukemia effect following allogeneic bone marrow transplantation. Br J Haematol 1985;61(4):749–751.Google Scholar
  5. Baron F, Storb R, Little MT. Hematopoietic cell transplantation: five decades of progress. Arch Med Res 2003;34(6):528–544.Google Scholar
  6. Barquet N, Domingo P. Smallpox: the triumph over the most terrible of the ministers of death. Ann Intern Med 1997;127(8 Pt 1):635–642.Google Scholar
  7. Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science 2004;305(5681):200–205.Google Scholar
  8. Brock MV, Borja MC, Ferber L, et al. Induction therapy in lung transplantation: A prospective, controlled clinical trial comparing OKT3, antithymocyte globulin, and daclizumab. J Heart Lung Transplant 2001; 20(12): 1282–1290.CrossRefGoogle Scholar
  9. Buckley RH. Primary cellular immunodeficiencies. J Allergy Clin Immunol 2002;109(5):747–757.Google Scholar
  10. Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 2001;358(9285):866–869.Google Scholar
  11. Childs RW, Barrett J. Nonmyeloablative allogeneic immunotherapy for solid tumors. Annu Rev Med 2004;55:459–475.Google Scholar
  12. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000;343(11): 750–758.Google Scholar
  13. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002;346(4):235–242.CrossRefGoogle Scholar
  14. Coyle TS, Nam TK, Camouse MM, Stevens SR, Baron ED. Steroid-sparing effect of extracorporeal photopheresis in the treatment of graft-vs-host disease. Arch Dermatol 2004;140(6):763–764.PubMedCrossRefGoogle Scholar
  15. Cunningham D, Humblet Y, Sienna S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351(4):337–345.CrossRefGoogle Scholar
  16. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med 2001; 345(5):340–350.PubMedCrossRefGoogle Scholar
  17. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298(5594):850–854.Google Scholar
  18. Francis RJ, Sharma SK, Springer C, et al. A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours. Br J Cancer 2002;87(6):600–607.CrossRefGoogle Scholar
  19. Gordon LI, Molina A, Witzig T, et al. Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+B-cell lymphoma: long-term follow-up of a phase 1/2 study. Blood 2004;103(12):4429–431.CrossRefGoogle Scholar
  20. Hiraoka A, Ohash Y, Okamoto S, et al. Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001;28(2):181–185.PubMedCrossRefGoogle Scholar
  21. Ho VT, Soiffer RJ. The history and future of T-cell depletion as graftversus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001;98(12):3192–3204.Google Scholar
  22. Holland SM. Update on phagocytic defects. Pediatr Infect Dis J 2003; 22(1):87, 88.Google Scholar
  23. Kalden JR, Schattenkirchner M, Sorensen H, et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year followup study. Arthritis Rheum 2003;48(6):1513–1520.CrossRefGoogle Scholar
  24. Kreitman RJ, Wilson WH, Bergeron K, et al. Efficacy of the anti-CD22 recombinant immunotoxin BL22 in chemotherapy-resistant hairy-cell leukemia. N Engl J Med 2001;345(4):241–247.CrossRefGoogle Scholar
  25. Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infections. Nat Med 2003;9(7):861–866.Google Scholar
  26. Leussink VI, Jung S, Merschdorf U, Toyka KV, Gold R. High-dose methylprednisolone therapy in multiple sclerosis induces apoptosis in peripheral blood leukocytes. Arch Neurol 2001;58(1):91–97.PubMedCrossRefGoogle Scholar
  27. Locatelli F, Bruno B, Zecca M, et al. Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood 2000;96(5): 1690–1697.Google Scholar
  28. Mikuls TR, Moreland LW. TNF blockade in the treatment of rheumatoid arthritis: Infliximab versus etanercept. Expert Opin Pharmacother 2001;2(1):75–84.Google Scholar
  29. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989;7:145–173.Google Scholar
  30. Nash RA, Antin JH, Karanes C, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 2000;96(6):2062–2068.Google Scholar
  31. Phan GQ, Yang JC, Sherry RM, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci USA 2003; 100(14):8372–8377.CrossRefGoogle Scholar
  32. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340(18): 1398–1405.CrossRefGoogle Scholar
  33. 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(7):2303–2314.Google Scholar
  34. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316(15):889–897.CrossRefGoogle Scholar
  35. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 1993;85(8):622–632.CrossRefGoogle Scholar
  36. Ruutu T, Volin L, Parkkali T, Juvonen E, Elonen E. Cyclosporine, methotrexate, and methylprednisolone compared with cyclosporine and methotrexate for the prevention of graft-versus-host disease in bone marrow transplantation from HLA-identical sibling donor: a prospective randomized study. Blood 2000;96(7):2391–2398.Google Scholar
  37. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343(4): 230–238.CrossRefGoogle Scholar
  38. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999;285(5426):412–415.CrossRefGoogle Scholar
  39. 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(12):729–735.CrossRefGoogle Scholar
  40. Suda T, Chida K, Matsuda H, et al. High-dose intravenous glucocorticoid therapy abrogates circulating dendritic cells. J Allergy Clin Immunol 2003;112(6):1237–1239.Google Scholar
  41. Van Lint MT, Uderzo C, Locasciulli A, et al. Early treatment of acute graft-versus-host disease with high-or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation. Blood 1998;92(7):2288–2293.Google Scholar
  42. Volpin R, Angeli P, Galioto A, et al. Comparison between two high-dose methylprednisolone schedules in the treatment of acute hepatic cellular rejection in liver transplant recipients: a controlled clinical trial. Liver Transpl 2002;8(6):527–534.CrossRefGoogle Scholar
  43. Washburn K, Speeg KV, Esterl R, et al. Steroid elimination 24 hours after liver transplantation using daclizumab, tacrolimus, and mycophenolate mofetil. Transplantation 2001;72(10): 1675–1679.CrossRefGoogle Scholar
  44. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340(4):253–259.CrossRefGoogle Scholar
  45. Weisdorf DJ, Nesbit ME, Ramsay NK, et al. Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease. J Clin Oncol 1987;5(9): 1348–1355.Google Scholar

Copyright information

© Humana Press Inc. 2006

Authors and Affiliations

  • Juan C. Gea-Banacloche
    • 1
  1. 1.Infectious Diseases Section, Experimental Transplantation and Immunology BranchNational Cancer InstituteBethesda

Personalised recommendations