Immunologic Research

, 38:174 | Cite as

Hematopoietic stem cell transplantation across major genetic barriers



The first successful demonstration that effective T cell depletion can enable immune reconstitution without causing graft versus host disease (GVHD) was achieved in 1980 using lectin-separated hematopoietic stem cells. In leukemia patients undergoing supralethal radio- and chemotherapy, T cell-depleted transplants are vigorously rejected by residual host T cells; this barrier was first overcome in 1993 by the use of megadose stem cell transplants. This clinical observation can be explained, in part, by the demonstration that cells within the CD34 compartments, as well as their immediate early myeloid progeny, are endowed with veto activity. Engraftment of mismatched hematopoietic stem cells following reduced intensity conditioning, still represents a major challenge. Progress has been made recently by using anti-3rd party veto CTLs and T regulatory cells.


Immune deficiency Leukemia Rejection Tolerance Veto 


  1. 1.
    Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Cunningham RS, Dupont B, et al. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood 1983;61:341–8.PubMedGoogle Scholar
  2. 2.
    Friedrich W, Goldmann S, Vetter U, Fliedner T, Heymer B, Peter H, et al. Immunoreconstitution in severe combined immunodeficiency after transplantation of HLA-haploidentical, T-cell-depleted bone marrow. Lancet 1984;1:761–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Fischer A, Durandy A, de Villartay JP, Vilmer E, Le Deist F, Gerota I, et al. HLA-Haploidentical bone marrow transplantation for severe combined immune deficiency using E-rosette fractionation and cyclosporine. Blood 1986;67:444–9.PubMedGoogle Scholar
  4. 4.
    Buckley RH, Schiff SE, Sampson HA, Schiff RI, Markert ML, Knutsen AP, et al. Development of immunity in human severe primary T cell deficiency following haploidentical bone marrow stem cell transplantation. J Immunol 1986;136:2398–407.PubMedGoogle Scholar
  5. 5.
    Reisner Y, Kapoor N, Pollack S, Friedrich W, Kirkpatrik D, Shank B, et al. Use of lectins in bone marrow transplantation. In: Recent advances in bone marrow transplantation. New York: Alan R. Liss, Inc.; 1983. p. 355–87.Google Scholar
  6. 6.
    Reisner Y, Kapoor N, O’Reilly RJ, Good RA. Allogeneic bone marrow transplantaation using stem cells fractionated by lectins: VI In vitro analysis of human and monkey bone marrow cells fractionated by sheep red blood cells and soybean agglutinin. Lancet 1980;ii:1320–4.CrossRefGoogle Scholar
  7. 7.
    Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Dupont B, Good RA, et al. Transplantation for acute leukaemia wih HLA-A and B non-identical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet 1981;2:327–31.PubMedCrossRefGoogle Scholar
  8. 8.
    O’Reilly RJ, ea. Hematopoietic cell transplantation. Malden: Blackwell Science; 2004.Google Scholar
  9. 9.
    Buckley RH, Sherrie E, Schiff BS, Schiff RI, Markert ML, Williams LW, Roberts JL, Myers LA, Ward FE. Hematopoietic stem cell transplantion for the treatment of severe combined immunodeficiency. New England J Med 1999;340:508–16.CrossRefGoogle Scholar
  10. 10.
    Gale RP, Reisner Y. Graft rejection and graft-versus-host disease: mirror images. Lancet 1986; 1:1468–70.PubMedGoogle Scholar
  11. 11.
    Kernan NA, Flomberg N, Dupont B, O'Reilly RJ. Graft rejection in recipients of T-cell-depleted HLA-nonidentical marrow transplants for leukemia. Identification of host-derived antidonor allocytotoxic T lymphocytes. Transplantation 1987;43:842–7.PubMedGoogle Scholar
  12. 12.
    Lapidot T, Terenzi A, Singer TS, Salomon O, Reisner Y. Enhancement by dimenthyl myleran of donor type chimerism in murine recipients of bone marrow allografts. Blood 1989;73:2025–32.PubMedGoogle Scholar
  13. 13.
    Lapidot T, Lubin I, Terenzi A, Faktorowich Y, Erlich P, Reisner Y. Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graaft-versus-host activity. Proc Natl Acad Sci 1990;87:4595–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Uharek L, Gassmann W, Glass B, Steinmann J, Mueller-Ruchholtz W. Influence of cell dose and graft-versus-host reactivity on rejection rats after allogeneic bone marrow transplantation. Blood 1992;79:1612–21.Google Scholar
  15. 15.
    Lubin I, Segall H, Erlich P, David M, Marcus H, Fire G, et al. Conversion of normal raats into SCID_like animals by means of bone marrow transplantation from SCID murine donor allows engraftment of human peripheral blood lymphocytes. Transplantation 1995;60:740–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1995;1:1268–73.PubMedCrossRefGoogle Scholar
  17. 17.
    Bachar-Lustig E, Li HW, Marcus H, Reisner Y. Tolerance induction by megadose stem cell transplants: synergism between Sca-1+Lin- cells and non-alloreactive T cells. Transplant Proc 1998;30:4007–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Sheridan WP, Glenn-Begley C, Juttner CA, Szer J, Nik T, Maher D, et al. Effect of periheral-blood progenitor cells mobilised by filgrastin (G-CSF) on platelet recovery after high-dose chemotherapy. Lancet 1992;339:640–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Bensinger W, Singer J, Appelbaum F, Lilleb K, Longin K, Rowley S, et al. Autologous transplantation with peripheral blood mononuclear cells collected after administration of recombinant granulocye stimulating factor. Blood 1993;81:3158–65.PubMedGoogle Scholar
  20. 20.
    Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Giannoni C, et al. Successful engraftment of T-cell-epleted haploidentical “three-loci” incompatible transplats in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood 1994;84:3948–55.PubMedGoogle Scholar
  21. 21.
    Reisner Y, Martelli MF. Bone marrow transplantation across HLA barriers by increaasing the number of transplanted cells. Immunol Today 1995;16:437–40.PubMedCrossRefGoogle Scholar
  22. 22.
    Lapidot T, Faktorowich Y, Lubin I, Reisner Y. Enhancement of T-cell-depleted bone marrow allografts in the absence of graft-versus-host disease is medited by CD8+CD4- and not by CD8-CD4+ thymocytes. Blood 1992;80:2406–11.PubMedGoogle Scholar
  23. 23.
    Cobbold SP, Martin G, Qin S, Waldman H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature 1986;323:164–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Strober S, Palathumpat V, Schwadron R, Hertel-Wulff B. Cloned natural suppressor cells prevent lethal graft-vs-host disease. J Immunol 1987;138:699–703.PubMedGoogle Scholar
  25. 25.
    Kikuya S, Inaba M, Ogata H, Yasumizu R, Inaba K. Wheat germ agglutinin-positive cells in a stem cell-enriched fraction of mouse bone marrow have potent natural suppressor activity. Proc Natl Acad Sci USA 1988;85:4824–6.CrossRefGoogle Scholar
  26. 26.
    Tscherning T, Claesson M. Veto-like down regulation of T helper cell reactivity in vivo by injection of semi-allogeneic spleen cells. Immunol Lett 1991;29:223–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Kiyoshi H, Kiruma K, Nakamura H, Henkart PA, Gress RE. Clonal deletion of postthymic T cells: veto cells kill precursor cytotoxic T lymphocytes. J Exp Med 1992;175:863–8.CrossRefGoogle Scholar
  28. 28.
    Pierce GE, Watts LM. Do donor cells function as veto cells in the induction and maintenance of tolerance across an MHC disparity in mixed lymphoid radiation chimeras? Transplantation 1993;55:882–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Pierce GE, Watts LM. Thy 1+ donor cells function as veto cells in the maintenance of tolerance across a major histocompatibility complex disparity in mixed-lymphoid radiation chimeras. Transplant Proc 1993;25:331–3.PubMedGoogle Scholar
  30. 30.
    Kaufman CL, Colson YL, Wren SM, Watkins S, Simmons RL, and Ildstad ST. Phenotypic chaaracterization of a novel bone marrow-derived cell that facilitates engraftment of allogeneic bone marrow stem cells. Blood 1994;84:2436–46.Google Scholar
  31. 31.
    Sambhara SR, Miller RG. Programmed cell death of T cells signaled by the T cell receptor and the alpha 3 domain of class I MHC. Science 1991;252:1424–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Thomas JM, Carver FM, Cunningham PR, Olson LC, Thomas FT. Kidney allograft tolerance in primates without chronic immunosuppression – the role of veto cells. Transplantation 1991;51:198–207.PubMedCrossRefGoogle Scholar
  33. 33.
    Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase ii study n patients with acute leukemia at high risk of relapse. J Clin Oncol 2005;23:3447–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Sanz MA, Sanz GF. Unrelated donor umbelical cord blood transplantation in adults. Leukemia 2002;16:1984–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Rocha V, Labopin M, Gluckman E. Transplants of umbilical-cord blood or bone marrow from unrelated donos in aduls with acute leukemia. N Engl J Med 2004;351:2276–85.Google Scholar
  36. 36.
    Sierra J, Storer B, Hansen JA, Anasetti C. Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience. Bone Marrow Transplant 2000;26:397–404.PubMedCrossRefGoogle Scholar
  37. 37.
    Laughlin MJ, Eapen M, Rubinstein P, Horowitz, MM. Outcomes after transplantaation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004;351:2265–75.PubMedCrossRefGoogle Scholar
  38. 38.
    Redei I, Langston A, Cherry J, Allen A, Bartlett V, Waller E. Haploidentical transplantation for adults with poor prognostic hematologic malignancies using the Perugia approach. Leukemia 2002;16:414.Google Scholar
  39. 39.
    Zuckerman T, Haddad N, Elhasis R, Rowe JM. Haploidentical transplantation – a single center experience. Leukemia 2002;16:417.Google Scholar
  40. 40.
    Handgretinger R, Klingebiel T, Lang P, Schumm M, Bader P, Schlegel P, et al. Haploidentical transplantation in children with hematological malignancies and non-malignant disorders. A single center 5-year experience. Leukemia 2002;16:410.Google Scholar
  41. 41.
    Cornish J, Goulden N, Sewaard C, Oakhill A. Haploidenticl stem cell transplantation in children. Leukemia 2002;6:408.Google Scholar
  42. 42.
    Klingebiel T, Lang P, Schumm M, Bader P, Schlegel P, Eyrich M, Greil J, et al. Haploidentical stem cell transplantation in children. Leukemia 2002;16:410.CrossRefGoogle Scholar
  43. 43.
    Rachamim N, Gan J, Segall H, Krauthgamer R, Marcus H, Berrebi A, et al. Tolerance induction by “megadose” hematopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation 1998;65:1386–93.PubMedCrossRefGoogle Scholar
  44. 44.
    Gur H, Krauthgamer R, Berrebi A, Klein T, Bagler A, Tabilio A, et al. Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34+ cells. Blood 2002;99:4174–81.PubMedCrossRefGoogle Scholar
  45. 45.
    Lenschow DJ, Zeng Y, Thistlethwaite JR, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA41g. Science 1992;257:789–92.PubMedCrossRefGoogle Scholar
  46. 46.
    Wekerle T, Kurtz J, Ito H, et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treaatment. Nat Med 2000;6:464–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Parker DC, Greiner DL, Phillips NE, et al. Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc Natl Acad Sci USA 1995;92:9560–4.Google Scholar
  48. 48.
    Honey K, Cobbold SP, Waldmann H. CD40 ligand blockade induces CD4+ T cell tolerance, linked suppression. J Immunol 1999;163:4805–10.PubMedGoogle Scholar
  49. 49.
    Judge TA, Wu Z, Zheng XG, et al. The role of CD80, CD86, and CTLA4 in alloimmune responses and the induction of long-term allograft survival. J Immunol 1999;162:1947–51.PubMedGoogle Scholar
  50. 50.
    Groux H, O’Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nat Med 1997;389:737–42.Google Scholar
  51. 51.
    Groux H, MBigler M, de Vries JE, Roncarolo MG. Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells. J Immunol 1998;160:3188–93.PubMedGoogle Scholar
  52. 52.
    Sakaguchi S, Sakaguchi N, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64.Google Scholar
  53. 53.
    Thornton AM, Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 1998;188:287–96.PubMedCrossRefGoogle Scholar
  54. 54.
    Cederbom L, Hall H, Ivars F. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol 2000;30:1538–43.PubMedCrossRefGoogle Scholar
  55. 55.
    Levings M., Sangregorio R, Roncarolo MG. Human CD25(+)CD4(+) T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193:1295–302.PubMedCrossRefGoogle Scholar
  56. 56.
    Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002;99:3493–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Rissoan MC, Soumelis V, Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183–6.PubMedCrossRefGoogle Scholar
  58. 58.
    Arpinati M, Green CL, Heimfeld S, et al. Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood 2000;95:2484–90.PubMedGoogle Scholar
  59. 59.
    He XY, Chen J, Hall BM. Treatment with interleukin-4 prolongs allogeneic neonatal heart graft survival by inducing T helper 2 responses. Transplantation 1998;65:1145–52.Google Scholar
  60. 60.
    Gur H, Krauthgamer R, Bachar-Lustig E, Katchman H, Arbel-Goren R, Berrebi A, et al. Immune regulatory activity of CD34+ progenitor cells: evidence for a deletion-based mechanism mediated by TNF-a. Blood 2005;105:2585–93.Google Scholar
  61. 61.
    Hiruma K, Nakamura H, Henkart PA, Gress RF. Clonal deletion of postthymic T cells: veto cells kill precursor sytotoxic T lymphocytes. J Exp Med 1992;175:83–8.CrossRefGoogle Scholar
  62. 62.
    Reich-Zeliger S, Zhao Y, Reisner Y. Anti-third party CD8+ CTLs as potent veto cells: co-expression of CD8 and FasL is a prerequisite. Immunity 2000;13:507–15.PubMedCrossRefGoogle Scholar
  63. 63.
    Sambhara SR, Miller RG. Reduction of CTL antipeptide response mediated by CD8+ cells whose class I MHC can bind the peptide. J Immunol 1994;152:1103–9.PubMedGoogle Scholar
  64. 64.
    Muraoka S, Miller RG. Cells in bone marrow and in T cell colonies grown from bone marrow can suppress generation of cytotoxic T lymphocytes directed against their self antigens. J Exp Med 1980;152:54–71.PubMedCrossRefGoogle Scholar
  65. 65.
    Claesson MH, Miller RG. Functional heterogeneity in allospecific cytotoxic T lymphocyte clones. I. CTL clones express strong anti-self suppressive activity. J Ex Med 1984;160:1702–16.CrossRefGoogle Scholar
  66. 66.
    Fink PH, Rammensee HG, Bevan MJ. Studies on the mechanism of suppression of primary cytotoxic responses by cloned cytotoxic T lymphocytes. J Immunol 1984;133:1769–74.Google Scholar
  67. 67.
    Verbanac KM, Carver FM, Haisch CE, Thomas JM. A role for transforming frowth factor-beta in the veto mechanism in transplant tolerance. Transplantation 1994;57:893–900.PubMedCrossRefGoogle Scholar
  68. 68.
    George JF, Sweeney SD, Kirklin JK, et al. An essential role for Fas ligand in transplantation tolerance induced by donor bone marrow. Nat Med 1998;4:333–5.PubMedCrossRefGoogle Scholar
  69. 69.
    Goldstein DR, Chang T, Sweeney SD, et al. A differential requirement for CD8+ donor cells in the augmentation of allograft survival by posttransplantation administration of donor spleen cells and donor bone marrow cells. Transplantation 2000;70:1068–73.PubMedCrossRefGoogle Scholar
  70. 70.
    Reich-Zeliger S, Gan J, Bachar-Lustig E, Reisner Y. Tolerance induction by veto CTLs in the TCR transgenic 2C mouse model: 1. Relative reactivity of different veto cells. J Immunology 2004;11:6660–6.Google Scholar
  71. 71.
    Reisner Y, Reich-Zeliger S, Bachar-Lustig E. The role of veto cells in bone marrow transplantation. Curr Opin Organ Transplant 2006;11:366–72.CrossRefGoogle Scholar
  72. 72.
    Maloney DG, Sandmaier BM, Mackinnon S, Shizuru JA. Non-myeloablative transplantation. Hematology (Am Soc Hemaatol Educ Program) 2002;392–421.Google Scholar
  73. 73.
    Bachar-Lustig E, Li HW, Gur H, et al. Induction of donor-type chimerism and transplantation tolerance across major histocompatibility barriers in sublethally rradiated mice by Sca-1(+)Lin(-) bone marrow progenitor cells: synergism with non-alloreaactive (Host x Donor)F(1) T cells. Blood 1999;94:3212–21.PubMedGoogle Scholar
  74. 74.
    Bachar-Lustig E, Reich-Zeliger S, Reisner Y. Anti-third party veto CTLs overcome rejection of hemaatopoietic allografts: synergism with rapamycim and BM cell dose. Blood 2003;102:1943–50.PubMedCrossRefGoogle Scholar
  75. 75.
    Aviner S, Yao X, Krauthgamer R, Gan Y, Goren-Arbel R, Klein T, et al. Large-scale preparation of human anti-third-party veto cytotoxic t lymphocytes depleted of graft-versus-host reaactivity: a new source for graft facilitating cells in bone marrow transplantation. Hum Immunol 2005;66:644–52.PubMedCrossRefGoogle Scholar
  76. 76.
    Shevach E. Certified professionals: CD4+CD25+ suppressor T cels. J Exp Med 2001;193:F41.PubMedCrossRefGoogle Scholar
  77. 77.
    Shevach E. Regulatory T cells in autoimmunity*. Annu Rev Immuol 2000;18:423.CrossRefGoogle Scholar
  78. 78.
    Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002;195:1641.PubMedCrossRefGoogle Scholar
  79. 79.
    Hara M, Kingsley CI, Niimi M, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens iin vivo. J Immunol 2001;166:3789.PubMedGoogle Scholar
  80. 80.
    Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1a, 25-dihydroyvitamin D3 and mycophenolate mofetil treatment mediate transplntation tolerance. J Immunol 2001;167:5058.Google Scholar
  81. 81.
    Chiffoleau E, Beriou G, Dutartre P, Ual C, Soulillou JP, Cuturi MC. Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cells iin allograft tolerance by L15–0195 treatment. J Immunol 2002;168:5058.PubMedGoogle Scholar
  82. 82.
    Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL. CD4+CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med 2002;196:401.PubMedCrossRefGoogle Scholar
  83. 83.
    Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host diseaase lethality. Blood 2002;196:389.Google Scholar
  84. 84.
    Steiner D, Brunicki N, Bachar-Lustig E, Taylor PA, Blazar BR, Reisner Y. Overcoming T cell-mediated rejection of bone marrow allografts by T-regulatory cells: Synergism with veto cells and rapamycin. Exp Hematol 2006;34:802–8.PubMedCrossRefGoogle Scholar
  85. 85.
    Steiner D, Brunicki N, Blazar BR, Bachar-Lustig E, Reisner Y. Tolerance induction by third-party “off-the-shef” CD4+CD25+ Treg cells. Exp Hematol 2005;34:66–71.CrossRefGoogle Scholar

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© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of ImmunologyWeizmann Institute of ScienceRehovotIsrael

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