Immunologic Research

, Volume 49, Issue 1–3, pp 49–55 | Cite as

Prevention of GVHD without losing GVL effect: windows of opportunity



Allogeneic hematopoietic cell transplantation has developed into a most successful form of immunotherapy for hematologic malignancies in the past 50 years. However, its effectiveness and wider applications have been greatly limited by the development of graft-versus-host disease (GVHD), a potentially lethal side effect associated with this procedure. Since the main effectors for both graft-versus-leukemia (GVL) effect and GVHD are T lymphocytes and these two processes share many similar pathways, it has not been easy to separate GVL from GVHD. Because the clinically used pan immunosuppressive therapy for GVHD prevention also results in decreased GVL effect, the success of allogeneic hematopoietic cell transplantation relies on a small and unpredictable therapeutic window at the present time. This review discusses how we may widen this therapeutic window so that we can reliably prevent GVHD without losing GVL effect.


Graft-versus-host disease Graft-versus-leukemia T lymphocytes Memory T cells Allogeneic hematopoietic stem cell transplantation 


  1. 1.
    De Vries MJ, Vos O. Treatment of mouse lymphosarcoma by total-body x-irradiation and by injection of bone marrow and lymph-node cells. J Natl Cancer Inst. 1958;21(6):1117–29.Google Scholar
  2. 2.
    Mathe G, Bernard J. Trial therapy, by x-irradiation followed by the administration of homologous bone marrow cells, of highly-advanced spontaneous leukemia in AK mice. Bull Assoc Fr Etud Cancer. 1958;45(3):289–300.PubMedGoogle Scholar
  3. 3.
    van Bekkum DW, de Vries VB. Radiation Cbimeras. London: Logos Ltd; 1967. p. 1–277.Google Scholar
  4. 4.
    Weiden PL, et al. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N Engl J Med. 1981;304(25):1529–33.PubMedCrossRefGoogle Scholar
  5. 5.
    Urbano-Ispizua A, et al. The number of donor CD3(+) cells is the most important factor for graft failure after allogeneic transplantation of CD34(+) selected cells from peripheral blood from HLA-identical siblings. Blood. 2001;97(2):383–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Urbano-Ispizua A, et al. Risk factors for acute graft-versus-host disease in patients undergoing transplantation with CD34 + selected blood cells from HLA-identical siblings. Blood. 2002;100(2):724–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Aversa F, 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):1186–93.PubMedCrossRefGoogle Scholar
  8. 8.
    Fowler DH, et al. Allospecific CD8 + Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol. 1996;157(11):4811–21.PubMedGoogle Scholar
  9. 9.
    Korngold R, Sprent J. T cell subsets and graft-versus-host disease. Transplantation. 1987;44(3):335–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Satake A, et al. Separation of antileukemic effects from graft-versus-host disease in MHC-haploidentical murine bone marrow transplantation: participation of host immune cells. Int J Hematol. 2010;91(3):485–97.PubMedCrossRefGoogle Scholar
  11. 11.
    Martin PJ, et al. A phase I–II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients. Blood. 1999;94(7):2192–9.PubMedGoogle Scholar
  12. 12.
    Nimer SD, et al. Selective depletion of CD8 + cells for prevention of graft-versus-host disease after bone marrow transplantation. A randomized controlled trial. Transplantation. 1994;57(1):82–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Champlin R, et al. Selective depletion of CD8-positive T-lymphocytes for allogeneic bone marrow transplantation: engraftment, graft-versus-host disease and graft-versus leukemia. Prog Clin Biol Res. 1992. 377:385–94; discussion 395–8.Google Scholar
  14. 14.
    Champlin R, et al. Selective depletion of CD8 + T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation. Blood. 1990;76(2):418–23.PubMedGoogle Scholar
  15. 15.
    Alyea EP, et al. Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood. 1998;91(10):3671–80.PubMedGoogle Scholar
  16. 16.
    Soiffer RJ, et al. Randomized trial of CD8 + T-cell depletion in the prevention of graft-versus-host disease associated with donor lymphocyte infusion. Biol Blood Marrow Transplant. 2002;8(11):625–32.PubMedCrossRefGoogle Scholar
  17. 17.
    Anderson BE, et al. Memory CD4 + T cells do not induce graft-versus-host disease. J Clin Invest. 2003;112(1):101–8.PubMedGoogle Scholar
  18. 18.
    Chen BJ, et al. Transfer of allogeneic CD62L—memory T cells without graft-versus-host disease. Blood. 2004;103(4):1534–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Li JM, et al. Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Immunotherapy. 2009;1(4):599–621.PubMedGoogle Scholar
  20. 20.
    Chakraverty R, et al. An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. J Exp Med. 2006;203(8):2021–31.PubMedCrossRefGoogle Scholar
  21. 21.
    Klingebiel T, Bader P. Delayed lymphocyte infusion in children given SCT. Bone Marrow Transplant. 2008;41(Suppl 2):S23–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Chakraverty R, et al. Host MHC class II + antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions. Blood. 2006;108(6):2106–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Billiau AD, et al. Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants. Blood. 2002;100(5):1894–902.PubMedCrossRefGoogle Scholar
  24. 24.
    Kernan NA, et al. Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease. Blood. 1986;68(3):770–3.PubMedGoogle Scholar
  25. 25.
    Mackinnon S, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood. 1995;86(4):1261–8.PubMedGoogle Scholar
  26. 26.
    Sad S, Mosmann TR. Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol. 1994;153(8):3514–22.PubMedGoogle Scholar
  27. 27.
    Sad S, Marcotte R, Mosmann TR. Cytokine-induced differentiation of precursor mouse CD8 + T cells into cytotoxic CD8 + T cells secreting Th1 or Th2 cytokines. Immunity. 1995;2(3):271–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Fowler DH, et al. Allospecific CD4 + , Th1/Th2 and CD8 + , Tc1/Tc2 populations in murine GVL: type I cells generate GVL and type II cells abrogate GVL. Biol Blood Marrow Transplant. 1996;2(3):118–25.PubMedGoogle Scholar
  29. 29.
    Yonemura Y, et al. Effects of interleukin-11 on carboplatin-induced thrombocytopenia in rats and in combination with stem cell factor. Int J Hematol. 1997;65(4):397–404.PubMedCrossRefGoogle Scholar
  30. 30.
    Krijanovski OI, et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood. 1999;94(2):825–31.PubMedGoogle Scholar
  31. 31.
    Antin JH, et al. A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation. Bone Marrow Transplant. 2002;29(5):373–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Couriel D, et al. Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood. 2004;104(3):649–54.PubMedCrossRefGoogle Scholar
  33. 33.
    Fowler DH, et al. Clinical “cytokine storm” as revealed by monocyte intracellular flow cytometry: correlation of tumor necrosis factor alpha with severe gut graft-versus-host disease. Clin Gastroenterol Hepatol. 2004;2(3):237–45.PubMedCrossRefGoogle Scholar
  34. 34.
    Ferrara JL, Abhyankar S, Gilliland DG. Cytokine storm of graft-versus-host disease: a critical effector role for interleukin-1. Transplant Proc. 1993;25(1 Pt 2):1216–7.PubMedGoogle Scholar
  35. 35.
    Hill GR, et al. Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia. J Clin Invest. 1999;104(4):459–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Korngold R, et al. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant. 2003;9(5):292–303.PubMedCrossRefGoogle Scholar
  37. 37.
    Taylor PA, et al. Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM). Blood. 2005;105(8):3372–80.PubMedCrossRefGoogle Scholar
  38. 38.
    Merad M, et al. Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat Med. 2004;10(5):510–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Chen W, et al. Cross-priming of CD8 + T cells by viral and tumor antigens is a robust phenomenon. Eur J Immunol. 2004;34(1):194–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Anderson BE, et al. Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood. 2005;105(5):2227–34.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Department of Medicine and ImmunologyDuke University Medical CenterDurhamUSA

Personalised recommendations