Cellular Adoptive Immunotherapy After Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

  • David L. PorterEmail author
  • Elizabeth O. Hexner
  • Sarah Cooley
  • Jeffrey S. Miller
Part of the Cancer Treatment and Research book series (CTAR, volume 144)


HSCT remains the best if not only curative therapy for many patients with hematologic malignancies. The success of HSCT is related not just to the high dose conditioning therapy, but at least in the setting of allogeneic HSCT, the donor graft itself can provide powerful “graft-versus-leukemia” (GvL) activity critically important for the cure of many patients. The relevant cellular immune components of the donor graft include at least T cells, natural killer (NK) cells and B cells, all recognized in various settings as potential effectors of the GvL (or graft-versus-tumor, GvT) effect. Although GvL activity was identified in some of the earliest murine models of HSCT [1], it took many years to unequivocally prove GvL activity was critical in clinical transplantation. Numerous observations implicated mature donor T cells as primarily mediators of GvL, and a tight association of GvL activity and graft-versus-host disease (GvHD) was repeatedly observed [2]. Ultimately, the...


Natural Killer Cell Chronic Myelogenous Leukemia Acute Myelogenous Leukemia Mesenchymal Stromal Cell Acute GvHD 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by grants from The Leukemia & Lymphoma Society (7000-02) and NIH (K24 CA11787901) (DLP) and P01 CA111412 and P01 CA65493 (JM).


  1.  1.
    Barnes D, Loutit J. Treatment of murine leukaemia with x-rays and homologous bone marrow. Br J Haematol. 1957;3:241–52.PubMedGoogle Scholar
  2.  2.
    Horowitz M, Gale R, Sondel P, Goldman J, Dersey J, Kolb H, Rimm A, Ringden O, Rozman C, Speck B, Truitt R, Zwaan F, Bortin M. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990;75:555–62.PubMedGoogle Scholar
  3.  3.
    Kolb H, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M, Wilmanns W. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990;76:2462–5.PubMedGoogle Scholar
  4.  4.
    Porter D, Roth M, McGarigle C, Ferrara J, Antin J. Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med. 1994;330:100–6.PubMedGoogle Scholar
  5.  5.
    Bacigalupo A, Soracco M, Vassallo F, Abate M, Van Lint MT, Gualandi F, Lamparelli T, Occhini D, Mordini N, Bregante S, Figari O, Benvenuto F, Sessarego M, Fugazza G, Carlier P, Valbonesi M. Donor lymphocyte infusions (DLI) in patients with chronic myeloid leukemia following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1997;19:927–32.PubMedGoogle Scholar
  6.  6.
    Kolb H, Schattenberg A, Goldman J, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995;86:2041–50.PubMedGoogle Scholar
  7.  7.
    Collins R, Shpilberg O, Drobyski W, Porter D, Giralt S, Champlin R, Goodman S, Wolff S, Hu W, Verfaillie C, List A, Dalton W, Ognoskie N, Chetrit A, Antin J, Nemunaitis J. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433–44.PubMedGoogle Scholar
  8.  8.
    Levine J, Braun T, Penza S, Beatty P, Cornetta K, Martino R, Drobyski W, Barrett A, Porter D, Giralt S, Horowitz M, Leis J, Johnson M, Collins R. Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem cell transplantation. J Clin Oncol. 2002;20:405–12.PubMedGoogle Scholar
  9.  9.
    Schmid C, Labopin M, Nagler A, Bornhauser M, Finke J, Fassas A, Volin L, Gurman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin NC, Kolb HJ, Rocha V. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. 2007;25:4938–45.PubMedGoogle Scholar
  10. 10.
    Choi SJ, Lee JH, Kim S, Seol M, Lee YS, Lee JS, Kim WK, Chi HS, Lee KH. Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia 2004;18:1789–97.PubMedGoogle Scholar
  11. 11.
    Collins RH Jr, Goldstein S, Giralt S, Levine J, Porter D, Drobyski W, Barrett J, Johnson M, Kirk A, Horowitz M, Parker P. Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant. 2000;26:511–16.PubMedGoogle Scholar
  12. 12.
    Campregher PV, Gooley T, Scott BL, Moravec C, Sandmaier B, Martin PJ, Deeg HJ, Warren EH, Flowers ME. Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation. Bone Marrow Transplant. 2007;40:965–71.PubMedGoogle Scholar
  13. 13.
    Lokhorst HM, Schattenberg A, Cornelissen JJ, Thomas LL, Verdonck LF. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood 1997;90:4206–11.PubMedGoogle Scholar
  14. 14.
    Lokhorst HM, Schattenberg A, Cornelissen JJ, van Oers MH, Fibbe W, Russell I, Donk NW, Verdonck LF. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol. 2000;18:3031–7.PubMedGoogle Scholar
  15. 15.
    Salama M, Nevill T, Marcellus D, Parker P, Johnson M, Kirk A, Porter D, Giralt S, Levine J, Drobyski W, Barrett A, Horowitz M, Collins R. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. 2000;26:1179–84.PubMedGoogle Scholar
  16. 16.
    Porter D, Collins R, Drobyski W, Connors J, Van Hoef M, Antin J. Long-term follow-up of 55 patients who achieved complete remission (CR) after donor leukocyte infusions (DLI) for relapse after allogeneic bone marrow transplantation (BMT). Blood 1997;90:549a.Google Scholar
  17. 17.
    Dazzi F, Szydlo RM, Cross NC, Craddock C, Kaeda J, Kanfer E, Cwynarski K, Olavarria E, Yong A, Apperley JF, Goldman JM. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood 2000;96:2712–6.PubMedGoogle Scholar
  18. 18.
    Porter D, Collins R, Shpilberg O, Drobyski W, Connors J, Sproles A, Antin J. Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions. Biol Blood Marrow Transplant. 1999;5:253–61.PubMedGoogle Scholar
  19. 19.
    Carlens S, Remberger M, Aschan J, Ringden O. The role of disease stage in the response to donor lymphocyte infusions as treatment for leukemic relapse. Biol Blood Marrow Transplant. 2001;7:31–8.PubMedGoogle Scholar
  20. 20.
    Gale R, Horowitz M, Ash R, Champlin R, Goldman J, Rimm A, Ringden O, Veum Stone J, Bortin M. Identical-twin bone marrow transplants for leukemia. Ann Intern Med. 1994;120:646–52.PubMedGoogle Scholar
  21. 21.
    Porter D, Roth M, Lee S, McGarigle C, Ferrara J, Antin J. Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation. Bone Marrow Transplant. 1996;18:975–80.PubMedGoogle Scholar
  22. 22.
    Szer J, Grigg A, Phillipos G, Sheridan W. Donor leucocyte infusions after chemotherapy for patients relapsing with acute leukaemia following allogeneic BMT. Bone Marrow Transplant. 1993;11:109–11.PubMedGoogle Scholar
  23. 23.
    Cunningham I. Extramedullary sites of leukemia relapse after transplant. Leuk Lymphoma. 2007;47:1754–67.Google Scholar
  24. 24.
    Chong G, Byrnes G, Szer J, Grigg A. Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy. Bone Marrow Transplant. 1011;26:1011–5.Google Scholar
  25. 25.
    Porter D, Antin J. Adoptive immunotherapy for relapsed leukemia following allogeneic bone marrow transplantation. Leuk Lymphoma. 1995;17:191–7.PubMedGoogle Scholar
  26. 26.
    Depil S, Deconinck E, Milpied N, Sutton L, Witz F, Jouet JP, Damaj G, Yakoub-Agha I, Societe Francaise de Greffe de Moelle et Therapie c. Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome. Bone Marrow Transplant. 2004;33:531–4.PubMedGoogle Scholar
  27. 27.
    Slavin S, Morecki S, Weiss L, Or R. Donor lymphocyte infusion: the use of alloreactive and tumor-reactive lymphocytes for immunotherapy of malignant and nonmalignant diseases in conjunction with allogeneic stem cell transplantation. J Hematother Stem Cell Res. 2002;11:265–76.PubMedGoogle Scholar
  28. 28.
    Choi SJ, Lee JH, Kim S, Lee YS, Seol M, Ryu SG, Lee JS, Kim WK, Jang S, Park CJ, Chi HS, Lee KH. Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study. Bone Marrow Transplant. 2005;36:163–9.PubMedGoogle Scholar
  29. 29.
    Bjorkstrand BB, Ljungman P, Svensson H, Hermans J, Alegre A, Apperley J, Blade J, Carlson K, Cavo M, Ferrant A, Goldstone AH, de Laurenzi A, Majolino I, Marcus R, Prentice HG, Remes K, Samson D, Sureda A, Verdonck LF, Volin L, Gahrton G. Allogeneic bone marrow transplantation versus autologous stem cell transplantation in multiple myeloma: a retrospective case-matched study from the European Group for Blood and Marrow Transplantation. Blood 1996;88:4711–8.PubMedGoogle Scholar
  30. 30.
    Badros A, Barlogie B, Morris C, Desikan R, Martin SR, Munshi N, Zangari M, Mehta J, Toor A, Cottler-Fox M, Fassas A, Anaissie E, Schichman S, Tricot G, Aniassie E. High response rate in refractory and poor-risk multiple myeloma after allotransplantation using a nonmyeloablative conditioning regimen and donor lymphocyte infusions. Blood 2001;97:2574–9.PubMedGoogle Scholar
  31. 31.
    Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omede P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356:1110–20.PubMedGoogle Scholar
  32. 32.
    Tricot G, Vesole D, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood 1996;87:1196–8.PubMedGoogle Scholar
  33. 33.
    Kroger N, Shimoni A, Zagrivnaja M, Ayuk F, Lioznov M, Schieder H, Renges H, Fehse B, Zabelina T, Nagler A, Zander AR. Low-dose thalidomide and donor lymphocyte infusion as adoptive immunotherapy after allogeneic stem cell transplantation in patients with multiple myeloma. Blood 2004;104:3361–3.PubMedGoogle Scholar
  34. 34.
    Ratanatharathorn V, Uberti J, Karanes C, Abella E, Lum LG, Momin F, Cummings G, Sensenbrenner LL. Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin’s lymphoma. Blood 1994;84:1050–5.PubMedGoogle Scholar
  35. 35.
    Jones R, Ambinder R, Piantadosi S, Santos G. Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 1991;77:649–53.PubMedGoogle Scholar
  36. 36.
    Bernard M, Dauriac C, Drenou B, Leberre C, Branger B, Fauchet R, Le Prise PY, Lamy T. Long-term follow-up of allogeneic bone marrow transplantation in patients with poor prognosis non-Hodgkin’s lymphoma. Bone Marrow Transplant. 1999;23:329–33.PubMedGoogle Scholar
  37. 37.
    Robinson S, Goldstone AH, Mackinnon S, Carella A, Russell N, DeElvira R, Taghipour G, Schmitz N. Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 2002;100:4310–6.PubMedGoogle Scholar
  38. 38.
    Porter D, Stadtmauer EA, Lazarus H. “GVHD”: graft-versus host disease or graft-versus Hodgkin’s disease? An old acronym with new meaning. Bone Marrow Transplant. 2003;31:739–46.PubMedGoogle Scholar
  39. 39.
    Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, Craddock C, Pettengell R, Dogan A, Thomson KJ, Morris EC, Hale G, Waldmann H, Goldstone AH, Linch DC, Mackinnon S. Clinical evidence of a graft-versus-Hodgkin’s-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet 2005;365:1934–41.PubMedGoogle Scholar
  40. 40.
    Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, Garcia-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Diez JL, Moraleda JM, Rubio-Felix D, Xicoy B, Martinez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin lymphoma: results of a Spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006;12:172–83.PubMedGoogle Scholar
  41. 41.
    Anderlini P, Champlin RE. Reduced intensity conditioning for allogeneic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: where do we stand? Biol Blood Marrow Transplant. 2006;12:599–602.PubMedGoogle Scholar
  42. 42.
    Loren A, Porter D. Donor leukocyte infusions after unrelated donor hematopoietic stem cell transplantation. Curr Opin Oncol. 2006;18:107–14.PubMedGoogle Scholar
  43. 43.
    van Rhee R, Savage D, Blackwell J, Orchard K, Dazzi F, Lin F, Chase A, Bungey J, Cross N, Apperley J, Szydlo R, Goldman J. Adoptive immunotherapy for relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: equal efficacy of lymphocytes from sibling and matched unrelated donors. Bone Marrow Transplant. 1998;21:1055–61.PubMedGoogle Scholar
  44. 44.
    Porter D, Collins R, Hardy C, Kernan N, Drobyski W, Giralt S, Flowers M, Casper J, Leahey A, Parker P, Mick R, Bate-Boyle B, King R, Antin J. Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. Blood 2000;95:1214–21.PubMedGoogle Scholar
  45. 45.
    Porter D, Antin J. Adoptive immunotherapy in bone marrow transplantation. In: Burakoff S, Deeg H, Ferrara J, editors. Graft-versus-host disease. New York: Marcel Dekker; 1997. p. 733–54.Google Scholar
  46. 46.
    Mackinnon S, Papadopoulos E, Carabasi M, Reich L, Collins N, Boulad F, Castro-Malaspina H, Childs B, Gillio A, Kernan N, Small T, Young J, O’Reilly R. 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;86:1261–8.PubMedGoogle Scholar
  47. 47.
    Porter D, Levine J. GVHD and GVL after donor leukocyte infusion. Semin Hematol. 2007;43:53–61.Google Scholar
  48. 48.
    Porter D, Antin J. Graft-versus-leukemia effect of allogeneic bone marrow transplantation and donor mononuclear cell infusions. In: Winter J, editor. Blood stem cell transplantation. Norwell: Kluwer Academic Publishers; 1997. p. 57–86.Google Scholar
  49. 49.
    Chiorean EG, DeFor TE, Weisdorf DJ, Blazar BR, McGlave PB, Burns LJ, Brown C, Miller JS. Donor chimerism does not predict response to donor lymphocyte infusion for relapsed chronic myelogenous leukemia after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2004;10:171–7.PubMedGoogle Scholar
  50. 50.
    Keil F, Haas OA, Fritsch G, Kalhs P, Lechner K, Mannhalter C, Reiter E, Niederwieser D, Hoecker P, Greinix HT. Donor leukocyte infusion for leukemic relapse after allogeneic marrow transplantation: lack of residual donor hematopoiesis predicts aplasia. Blood 1997;89:3113–7.PubMedGoogle Scholar
  51. 51.
    Flowers M, Leisenring W, Beach K, Riddell S, Radich J, Higano C, Rowley S, Chauncey T, Bensinger W, Sanders J, Anasetti C, Storb R, Wade J, Appelbaum F, Martin P. Granulocyte colony-stimulating factor given to donors before apheresis does not prevent aplasia in patients treated with donor leukocyte infusion for recurrent chronic myeloid leukemia after bone marrow transplantation. Biol Blood Marrow Transplant. 2000;6:321–6.PubMedGoogle Scholar
  52. 52.
    Gustafsson A, Levitsky V, Zou JZ, Frisan T, Dalianis T, Ljungman P, Ringden O, Winiarski J, Ernberg I, Masucci MG. Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells. Blood 2000;95:807–14.PubMedGoogle Scholar
  53. 53.
    Loren AW, Porter DL, Stadtmauer EA, Tsai DE. Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant. 2003;31:145–55.PubMedGoogle Scholar
  54. 54.
    Shapiro R, McClain K, Frizzera G, Gajl-Peczalska K, Kersey J, Blazar B, Arthur D, Patton D, Greenberg J, Burke B, Ramsay N, McGlave P, Filipovich A. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 1988;71:1234–43.PubMedGoogle Scholar
  55. 55.
    Porter D, Orloff G, Antin J. Donor mononuclear cell infusions as therapy for B-cell lymphoproliferative disorder following allogeneic bone marrow transplant. Transplant Sci. 1994;4:11–15.Google Scholar
  56. 56.
    Papadopoulos E, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi M, Castro-Malaspina J, Childs B, Gillio A, Small T, Young J, Kernan N, O’Reilly R. Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med. 1994;330:1185–91.PubMedGoogle Scholar
  57. 57.
    Rooney C, Smith C, Ng C, Loftin S, Sixbey J, Gan Y, Srivastava DK, Bowman L, Krance R, Brenner M, Heslop H. Infusion of cytoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 1998;92:1549–55.PubMedGoogle Scholar
  58. 58.
    Riddell S, Watanabe K, Goodrich J, Li C, Agha M, Greenberg P. Restoration of viral immunity in immunodeficient humans by adoptive transfer of T cell clones. Science 1992;257:238–41.PubMedGoogle Scholar
  59. 59.
    Walter E, Greenberg P, Gilbert M, Finch R, Watanabe K, Thomas E, Riddell S. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995;333:1038–44.PubMedGoogle Scholar
  60. 60.
    Hromas R, Cornetta K, Srour E. Donor leukocyte infusion as therapy of life-threatening adenoviral infections after T-cell-depleted bone marrow transplantation. Blood 1994;84(5):1689–90.Google Scholar
  61. 61.
    Kishi Y, Kami M, Oki Y, Kazuyama Y, Kawabata M, Miyakoshi S, Morinaga S, Suzuki R, Mori S, Muto Y. Donor lymphocyte infusion for treatment of life-threatening respiratory syncytial virus infection following bone marrow transplantation. Bone Marrow Transplant. 2000;26:573–6.PubMedGoogle Scholar
  62. 62.
    Guglielmi C, Arcese W, Dazzi F, Brand R, Bunjes D, Verdonck LF, Schattenberg A, Kolb HJ, Ljungman P, Devergie A, Bacigalupo A, Gomez M, Michallet M, Elmaagacli A, Gratwohl A, Apperley J, Niederwieser D. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood 2002;100:397–405.PubMedGoogle Scholar
  63. 63.
    Sullivan K, Weiden P, Storb R, Witherspoon R, Fefer A, Fisher L, Buckner C, Anasetti C, Appelbaum F, Badger C, Beatty P, Bensinger W, Berenson R, Bigelow C, Cheever M, Clift R, Deeg H, Doney K, Greenberg P, Hansen J, Hill R, Loughran T, Martin P, Neiman P, Peterson F, Sanders J, Singer J, Stewart P, Thomas E. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989;73:1720–8.PubMedGoogle Scholar
  64. 64.
    Johnson B, Drobyski W, Truitt R. Delayed infusion of normal donor cells after MHC-matched bone marrow transplantation provides an antileukemia reaction without graft-versus-host disease. Bone Marrow Transplant. 1993;11:329–36.PubMedGoogle Scholar
  65. 65.
    Weiden P, Storb R, Tsoi M, Graham T, Lerner K, Thomas E. Infusion of donor lymphocytes into stable canine radiation chimeras: implications for mechanism of transplantation tolerance. J Immunol. 1978;116:1212–9.Google Scholar
  66. 66.
    Alyea E, Soiffer R, Canning C, Neuberg D, Schlossman R, Pickett C, Collins H, Wang Y, Anderson K, Ritz J. Toxicity and efficacy of defined doses of CD4+ donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998;91:3671–80.PubMedGoogle Scholar
  67. 67.
    Giralt S, Hester J, Huh Y, Hirsch-Ginsberg C, Rondon G, Seong D, Lee M, Gajewski J, Van Besien K, Khouri I, Mehra R, Przepiorka D, Korbling M, Talpaz M, Kantarjian H, Fischer H, Deisseroth A, Champlin R. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995;86:4337–43.PubMedGoogle Scholar
  68. 68.
    Shimoni A, Gajewski J, Donato M, Martin T, O’Brien S, Talpaz M, Cohen A, Korbling M, Champlin R, Giralt S. Long-term follow-up of recipients of CD8 depleted donor lymphocyte infusions for the treatment of chronic myelogenous leukemia relapsing after allogeneic progenitor cell transplantation. Biol Blood Marrow Transplant. 2001;7:568–75.PubMedGoogle Scholar
  69. 69.
    Waller EK, Ship AM, Mittelstaedt S, Murray TW, Carter R, Kakhniashvili I, Lonial S, Holden JT, Boyer MW. Irradiated donor leukocytes promote engraftment of allogeneic bone marrow in major histocompatibility complex mismatched recipients without causing graft-versus-host disease. Blood 1999;94:3222–33.PubMedGoogle Scholar
  70. 70.
    Truitt RL, Johnson BD, Hanke C, Talib S, Hearst JE. Photochemical treatment with S-59 psoralen and ultraviolet: a light to control the fate of naive or primed T lymphocytes in vivo after allogeneic bone marrow transplantation. J Immunol. 1999;163:5145–56.PubMedGoogle Scholar
  71. 71.
    Servida P, Rossini S, Traversari C, Ferrari G, Bonini C, Nobili N, Vago L, Faravelli A, Vanzulli A, Mavillio F, Bordignon C. Gene transfer into peripheral blood lymphocytes for in vivo immunomodulation of donor anti-tumor immunity in a patient affected by EBV-induced lymphoma. Blood 1993;82:214a.Google Scholar
  72. 72.
    Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Mavilio F, Traversari C, Bordignon C. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 1997;276:1719–24.PubMedGoogle Scholar
  73. 73.
    Falkenburg JH, Wafelman AR, Joosten P, Smit WM, van Bergen CA, Bongaerts R, Lurvink E, van der Hoorn M, Kluck P, Landegent JE, Kluin-Nelemans HC, Fibbe WE, Willemze R. Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. Blood 1999;94:1201–8.PubMedGoogle Scholar
  74. 74.
    Cardoso AA, Seamon MJ, Afonso HM, Ghia P, Boussiotis VA, Freeman GJ, Gribben JG, Sallan SE, Nadler LM. Ex vivo generation of human anti-pre-B leukemia-specific autologous cytolytic T cells. Blood 1997;90:549–61.PubMedGoogle Scholar
  75. 75.
    Kolb HJ, Schmid C, Barrett AJ, Schendel DJ. Graft-versus-leukemia reactions in allogeneic chimeras. Blood 2004;103:767–76.PubMedGoogle Scholar
  76. 76.
    Bocchia M, Korontsvit T, Xu Q, Mackinnon S, Yang SY, Sette A, Scheinberg DA. Specific human cellular immunity to bcr-abl oncogene-derived peptides. Blood 1996;87:3587–92.PubMedGoogle Scholar
  77. 77.
    Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, Macintyre AR, Rojas J, Bourdon A, Bonner PL, Wang L, Christmas SE, Travers PJ, Creaser CS, Rees RC, Madrigal JA. Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood 2001;98:2887–93.PubMedGoogle Scholar
  78. 78.
    Voogt PJ, Goulmy E, Veenhof WF, Hamilton M, Fibbe WE, Van Rood JJ, Falkenburg JH. Cellularly defined minor histocompatibility antigens are differentially expressed on human hematopoietic progenitor cells. J Exp Med. 1988;168:2337–47.PubMedGoogle Scholar
  79. 79.
    Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E. Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. Blood 1999;93:2336–41.PubMedGoogle Scholar
  80. 80.
    Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA, van Luxemburg-Heys SA, Hoogeboom M, Mutis T, Drijfhout JW, van Rood JJ, Willemze R, Falkenburg JH. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA. 2003;100:2742–7.Google Scholar
  81. 81.
    Miklos DB, Kim HT, Zorn E, Hochberg EP, Guo L, Mattes-Ritz A, Viatte S, Soiffer RJ, Antin JH, Ritz J. Antibody response to DBY minor histocompatibility antigen is induced after allogeneic stem cell transplantation and in healthy female donors. Blood 2004;103:353–9.PubMedGoogle Scholar
  82. 82.
    Randolph SS, Gooley TA, Warren EH, Appelbaum FR, Riddell SR. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants. Blood 2004;103:347–52.PubMedGoogle Scholar
  83. 83.
    Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, Fukushima P, Barrett AJ. Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 1996;88:2450–7.PubMedGoogle Scholar
  84. 84.
    Molldrem JJ, Lee PP, Wang C, Felio K, Kantarjian HM, Champlin RE, Davis MM. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med. 2000;6:1018–23.PubMedGoogle Scholar
  85. 85.
    Heslop HE, Stevenson FK, Molldrem JJ. Immunotherapy of hematologic malignancy. Hematology Am Soc Hematol Educ Program. 2003: 331–49.Google Scholar
  86. 86.
    Rosenfeld C, Cheever MA, Gaiger A. WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies. Leukemia 2003;17:1301–12.PubMedGoogle Scholar
  87. 87.
    Atanackovic D, Arfsten J, Cao Y, Gnjatic S, Schnieders F, Bartels K, Schilling G, Faltz C, Wolschke C, Dierlamm J, Ritter G, Eiermann T, Hossfeld DK, Zander AR, Jungbluth AA, Old LJ, Bokemeyer C, Kroger N. Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation. Blood 1103;109:1103–12.Google Scholar
  88. 88.
    Greiner J, Schmitt M, Li L, Giannopoulos K, Bosch K, Schmitt A, Dohner K, Schlenk RF, Pollack JR, Dohner H, Bullinger L. Expression of tumor-associated antigens in acute myeloid leukemia: implications for specific immunotherapeutic approaches. Blood 2006;108:4109–17.PubMedGoogle Scholar
  89. 89.
    Pinilla-Ibarz J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, Lai L, Jimenez J, Kolitz J, Scheinberg DA. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood 2000;95:1781–7.PubMedGoogle Scholar
  90. 90.
    Miller JS, Weisdorf DJ, Burns LJ, Slungaard A, Wagner JE, Verneris MR, Cooley S, Wangen R, Fautsch SK, Nicklow R, Defor T, Blazar BR. Lymphodepletion followed by donor lymphocyte infusion (DLI) causes significantly more acute graft-versus-host disease than DLI alone. Blood 2007;110:2761–3.PubMedGoogle Scholar
  91. 91.
    Liebowitz D, Lee K, CH J. Costimulatory approaches to adoptive immunotherapy. Curr Opin Oncol. 1998;10:533–41.PubMedGoogle Scholar
  92. 92.
    Levine BL, Bernstein WB, Connors M, Craighead N, Lindsten T, Thompson CB, June CH. Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol. 1997;159:5921–30.PubMedGoogle Scholar
  93. 93.
    Porter DL, Levin BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S, Loren A, Phillips J, Nasta S, Perl A, Schuster S, Tsai D, Sohal A, Veloso E, Emerson S, June CH. A Phase I trial of donor lymphocyte infusions expanded and activated ex-vivo via CD3/CD28 co-stimulation. Blood 2006;107(4):1325–31.Google Scholar
  94. 94.
    Fowler DH, Odom J, Steinberg SM, Chow CK, Foley J, Kogan Y, Hou J, Gea-Banacloche J, Sportes C, Pavletic S, Leitman S, Read EJ, Carter C, Kolstad A, Fox R, Beatty GL, Vonderheide RH, Levine BL, June CH, Gress RE, Bishop MR. Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2006;12:1150–60.PubMedGoogle Scholar
  95. 95.
    Guillaume T, Rubinstein DB, Symann M. Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood 1998;92:1471–90.PubMedGoogle Scholar
  96. 96.
    Porrata LF, Gertz MA, Litzow MR, Lacy MQ, Dispenzieri A, Inwards DJ, Ansell SM, Micallef IN, Gastineau DA, Elliott M, Hogan WJ, Hayman SR, Tefferi A, Markovic SN. Early lymphocyte recovery predicts superior survival after autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis. Clin Cancer Res. 2005;11:1210–8.PubMedGoogle Scholar
  97. 97.
    Boulassel MR, Herr AL, de BEMD, Galal A, Lachance S, Laneuville P, Routy JP. Early lymphocyte recovery following autologous peripheral stem cell transplantation is associated with better survival in younger patients with lymphoproliferative disorders. Hematology 2006;11:165–70.PubMedGoogle Scholar
  98. 98.
    Laport GG, Levine BL, Stadtmauer EA, Schuster SJ, Luger SM, Grupp S, Bunin N, Strobl FJ, Cotte J, Zheng Z, Gregson B, Rivers P, Vonderheide RH, Liebowitz DN, Porter DL, June CH. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood 2003;102:2004–13.PubMedGoogle Scholar
  99. 99.
    Rapoport A, Stadtmauer E, Aqui N, Badros A, Cotte J, Chrisley L, Velosa E, Zheng Z, Westphal S, Mair R, Chi N, Ratterree B, Pochran M, Natt S, Hinkle J, Sickles C, Sohal A, Ruehle K, Lynch C, Zhang L, Porter D, Luger S, Guo C, Fang H, Blackwelder W, Hankey M, Mann D, Edelman R, Frasch C, Levine B, Cross A, June C. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med. 2005;11:1230–7.PubMedGoogle Scholar
  100. 100.
    Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23:225–74.PubMedGoogle Scholar
  101. 101.
    Herberman RB, Ortaldo JR. Natural killer cells: their roles in defenses against disease. Science 1981;214:24–30.PubMedGoogle Scholar
  102. 102.
    Kiessling R, Petranyi G, Klein G, Wigzel H. Genetic variation of in vitro cytolytic activity and in vivo rejection potential of non-immunized semi-syngeneic mice against a mouse lymphoma line. Int J Cancer. 1975;15:933–40.PubMedGoogle Scholar
  103. 103.
    Murphy WJ, Kumar V, Bennett M. Acute rejection of murine bone marrow allografts by natural killer cells and T cells. Differences in kinetics and target antigens recognized. J Exp Med. 1987;166:1499–509.PubMedGoogle Scholar
  104. 104.
    Cudkowicz G, Bennett M. Peculiar immunobiology of bone marrow allografts. II. Rejection of parental grafts by resistant F1 hybrid mice. J Exp Med. 1971;134:1513–28.PubMedGoogle Scholar
  105. 105.
    Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–40.PubMedGoogle Scholar
  106. 106.
    Rayner AA, Grimm EA, Lotze MT, Chu EW, Rosenberg SA. Lymphokine-activated killer (LAK) cells. Analysis of factors relevant to the immunotherapy of human cancer. Cancer 1985;55:1327–33.PubMedGoogle Scholar
  107. 107.
    Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, Anderson D, Eisenmann J, Grabstein K, Caligiuri MA. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994;180:1395–403.PubMedGoogle Scholar
  108. 108.
    Trinchieri G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003;3:133–46.PubMedGoogle Scholar
  109. 109.
    Young HA, Ortaldo J. Cytokines as critical co-stimulatory molecules in modulating the immune response of natural killer cells. Cell Res. 2006;16:20–24.PubMedGoogle Scholar
  110. 110.
    Singh SM, Yanagawa H, Hanibuchi M, Miki T, Okamura H, Sone S. Augmentation by interleukin-18 of MHC-nonrestricted killer activity of human peripheral blood mononuclear cells in response to interleukin-12. Int J Immunopharmacol. 2000;22:35–43.PubMedGoogle Scholar
  111. 111.
    Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural-killer cells and dendritic cells: “l’union fait la force”. Blood 2005;106:2252–8.PubMedGoogle Scholar
  112. 112.
    Re F, Staudacher C, Zamai L, Vecchio V, Bregni M. Killer cell Ig-like receptors ligand-mismatched, alloreactive natural killer cells lyse primary solid tumors. Cancer 2006;107:640–8.PubMedGoogle Scholar
  113. 113.
    Armeanu S, Bitzer M, Lauer UM, Venturelli S, Pathil A, Krusch M, Kaiser S, Jobst J, Smirnow I, Wagner A, Steinle A, Salih HR. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 2005;65:6321–9.PubMedGoogle Scholar
  114. 114.
    Russell JH, Ley TJ. Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002;20:323–70.PubMedGoogle Scholar
  115. 115.
    Lanier LL, Ruitenberg JJ, Phillips JH. Functional and biochemical analysis of CD16 antigen on natural killer cells and granulocytes. J Immunol. 1988;141:3478–85.PubMedGoogle Scholar
  116. 116.
    Marsh SG, Parham P, Dupont B, Geraghty DE, Trowsdale J, Middleton D, Vilches C, Carrington M, Witt C, Guethlein LA, Shilling H, Garcia CA, Hsu KC, Wain H. Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002. Tissue Antigens 2003;62:79–86.PubMedGoogle Scholar
  117. 117.
    Yawata M, Yawata N, Abi-Rached L, Parham P. Variation within the human killer cell immunoglobulin-like receptor (KIR) gene family. Crit Rev Immunol. 2002;22:463–82.PubMedGoogle Scholar
  118. 118.
    Pando MJ, Gardiner CM, Gleimer M, McQueen KL, Parham P. The protein made from a common allele of KIR3DL1 (3DL1*004) is poorly expressed at cell surfaces due to substitution at positions 86 in Ig domain 0 and 182 in Ig domain 1. J Immunol. 2003;171:6640–9.PubMedGoogle Scholar
  119. 119.
    Yokoyama WM, Daniels BF, Seaman WE, Hunziker R, Margulies DH, Smith HR. A family of murine NK cell receptors specific for target cell MHC class I molecules. Semin Immunol. 1995;7:89–101.PubMedGoogle Scholar
  120. 120.
    Vales-Gomez M, Reyburn HT, Mandelboim M, Strominger JL. Kinetics of interaction of HLA-C ligands with natural killer cell inhibitory receptors. Immunity 1998;9:337–44.PubMedGoogle Scholar
  121. 121.
    Houchins JP, Yabe T, McSherry C, Bach FH. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J Exp Med. 1991;173:1017–20.PubMedGoogle Scholar
  122. 122.
    Lopez-Botet M, Angulo A, Guma M. Natural killer cell receptors for major histocompatibility complex class I and related molecules in cytomegalovirus infection. Tissue Antigens. 2004;63:195–203.PubMedGoogle Scholar
  123. 123.
    Cao W, Xi X, Hao Z, Li W, Kong Y, Cui L, Ma C, Ba D, He W. RAET1E2, a soluble isoform of the UL16 binding protein RAET1E produced by tumor cells, inhibits NKG2D-mediated NK cytotoxicity. J Biol Chem. 2007;282:18922–8.PubMedGoogle Scholar
  124. 124.
    Ljunggren HG, Karre K. In search of the ”missing self”: MHC molecules and NK cell recognition. Immunol Today. 1990;11:237–44.PubMedGoogle Scholar
  125. 125.
    Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D’Andrea A, Phillips JH, Lanier LL, Parham P. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity 1997;7:739–51.PubMedGoogle Scholar
  126. 126.
    Raulet DH, Vance RE, McMahon CW. Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol. 2001;19:291–330.PubMedGoogle Scholar
  127. 127.
    Fernandez NC, Treiner E, Vance RE, Jamieson AM, Lemieux S, Raulet DH. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules. Blood 2005;105:4416–23.PubMedGoogle Scholar
  128. 128.
    Anfossi N, Andre P, Guia S, Falk CS, Roetynck S, Stewart CA, Breso V, Frassati C, Reviron D, Middleton D, Romagne F, Ugolini S, Vivier E. Human NK cell education by inhibitory receptors for MHC class I. Immunity 2006;25:331–42.PubMedGoogle Scholar
  129. 129.
    Cooley S, Xiao F, Pitt M, Gleason M, McCullar V, Bergemann T, McQueen KL, Guethlein LA, Parham P, Miller JS. A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self MHC is developmentally immature. Blood 2007;110:578–86.PubMedGoogle Scholar
  130. 130.
    Farrell HE, Vally H, Lynch DM, Fleming P, Shellam GR, Scalzo AA, Davis-Poynter NJ. Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature 1997;386:510–4.PubMedGoogle Scholar
  131. 131.
    Voigt V, Forbes CA, Tonkin JN, Degli-Esposti MA, Smith HR, Yokoyama WM, Scalzo AA. Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells. Proc Natl Acad Sci USA. 2003;100:13483–8.Google Scholar
  132. 132.
    Martin MP, Qi Y, Gao X, Yamada E, Martin JN, Pereyra F, Colombo S, Brown EE, Shupert WL, Phair J, Goedert JJ, Buchbinder S, Kirk GD, Telenti A, Connors M, O’Brien SJ, Walker BD, Parham P, Deeks SG, McVicar DW, Carrington M. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat Genet. 2007;39:733–40.PubMedGoogle Scholar
  133. 133.
    Trinchieri G, Sher A. Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol. 2007;7:179–90.PubMedGoogle Scholar
  134. 134.
    Miller JS, McCullar V. Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2. Blood 2001;98:705–13.PubMedGoogle Scholar
  135. 135.
    Yu H, Fehniger TA, Fuchshuber P, Thiel KS, Vivier E, Carson WE, Caligiuri MA. Flt3 ligand promotes the generation of a distinct CD34(+) human natural killer cell progenitor that responds to interleukin-15. Blood 1998;92:3647–57.PubMedGoogle Scholar
  136. 136.
    Muench MO, Humeau L, Paek B, Ohkubo T, Lanier LL, Albanese CT, Barcena A. Differential effects of interleukin-3, interleukin-7, interleukin 15, and granulocyte-macrophage colony-stimulating factor in the generation of natural killer and B cells from primitive human fetal liver progenitors. Exp Hematol. 2000;28:961–73.PubMedGoogle Scholar
  137. 137.
    Freud AG, Yokohama A, Becknell B, Lee MT, Mao HC, Ferketich AK, Caligiuri MA. Evidence for discrete stages of human natural killer cell differentiation in vivo. J Exp Med. 2006;203:1033–43.PubMedGoogle Scholar
  138. 138.
    Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol. 2005;174:2591–601.PubMedGoogle Scholar
  139. 139.
    Trompeter HI, Gomez-Lozano N, Santourlidis S, Eisermann B, Wernet P, Vilches C, Uhrberg M. Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3. J Immunol. 2005;174:4135–43.PubMedGoogle Scholar
  140. 140.
    Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, Tyan D, Lanier LL, Parham P. Human diversity in killer cell inhibitory receptor genes. Immunity 1997;7:753–63.PubMedGoogle Scholar
  141. 141.
    Kikuchi-Maki A, Yusa S, Catina TL, Campbell KS. KIR2DL4 is an IL-2-regulated NK cell receptor that exhibits limited expression in humans but triggers strong IFN-gamma production. J Immunol. 2003;171:3415–25.PubMedGoogle Scholar
  142. 142.
    Maxwell LD, Wallace A, Middleton D, Curran MD. A common KIR2DS4 deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey. Tissue Antigens 2002;60:254–8.PubMedGoogle Scholar
  143. 143.
    Leung W, Iyengar R, Triplett B, Turner V, Behm FG, Holladay MS, Houston J, Handgretinger R. Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. J Immunol. 2005;174:6540–5.PubMedGoogle Scholar
  144. 144.
    Cooley S, McCullar V, Wangen R, Bergemann TL, Spellman S, Weisdorf DJ, Miller JS. KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation. Blood 2005;106:4370–6.PubMedGoogle Scholar
  145. 145.
    Gasser S, Raulet DH. Activation and self-tolerance of natural killer cells. Immunol Rev. 2006;214:130–42.PubMedGoogle Scholar
  146. 146.
    Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ, Lee SJ, Windawi S, Ritz J, Stone RM, Antin JH, Soiffer RJ. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005;105:1810–4.PubMedGoogle Scholar
  147. 147.
    Yokoyama WM, Kim S. Licensing of natural killer cells by self-major histocompatibility complex class I. Immunol Rev. 2006;214:143–54.PubMedGoogle Scholar
  148. 148.
    Parham P. Taking license with natural killer cell maturation and repertoire development. Immunol Rev. 2006;214:155–60.PubMedGoogle Scholar
  149. 149.
    Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, 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;316:889–97.PubMedGoogle Scholar
  150. 150.
    Burns LJ, Weisdorf DJ, DeFor TE, Vesole DH, Repka TL, Blazar BR, Burger SR, Panoskaltsis-Mortari A, Keever-Taylor CA, Zhang MJ, Miller JS. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial. Bone Marrow Transplant. 2003;32:177–86.PubMedGoogle Scholar
  151. 151.
    Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA, Theofilopoulos AN. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest. 2002;110:185–92.PubMedGoogle Scholar
  152. 152.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002;298:850–4.PubMedGoogle Scholar
  153. 153.
    Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002;295:2097–100.PubMedGoogle Scholar
  154. 154.
    Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, Restifo NP. Increased intensity lymphodepletion and adoptive immunotherapy – how far can we go? Nat Clin Pract Oncol. 2006;3:668–81.PubMedGoogle Scholar
  155. 155.
    Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005;105:3051–7.PubMedGoogle Scholar
  156. 156.
    Cooley S, Burns LJ, Repka T, Miller JS. Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu. Exp Hematol. 1999;27:1533–41.PubMedGoogle Scholar
  157. 157.
    Igarashi T, Wynberg J, Srinivasan R, Becknell B, McCoy JP Jr, Takahashi Y, Suffredini DA, Linehan WM, Caligiuri MA, Childs RW. Enhanced cytotoxicity of allogeneic NK cells with killer immunoglobulin-like receptor ligand incompatibility against melanoma and renal cell carcinoma cells. Blood 2004;104:170–7.PubMedGoogle Scholar
  158. 158.
    Ohira M, Ohdan H, Mitsuta H, Ishiyama K, Tanaka Y, Igarashi Y, Asahara T. Adoptive transfer of TRAIL-expressing natural killer cells prevents recurrence of hepatocellular carcinoma after partial hepatectomy. Transplantation 2006;82:1712–9.PubMedGoogle Scholar
  159. 159.
    Passweg JR, Tichelli A, Meyer-Monard S, Heim D, Stern M, Kuhne T, Favre G, Gratwohl A. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 2004;18:1835–8.PubMedGoogle Scholar
  160. 160.
    Koehl U, Esser R, Zimmermann S, Tonn T, Kotchetkov R, Bartling T, Sorensen J, Gruttner HP, Bader P, Seifried E, Martin H, Lang P, Passweg JR, Klingebiel T, Schwabe D. Ex vivo expansion of highly purified NK cells for immunotherapy after haploidentical stem cell transplantation in children. Klin Padiatr. 2005;217:345–50.PubMedGoogle Scholar
  161. 161.
    Koh CY, Blazar BR, George T, Welniak LA, Capitini CM, Raziuddin A, Murphy WJ, Bennett M. Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo. Blood 2001;97:3132–7.PubMedGoogle Scholar
  162. 162.
    Barao I, Hanash AM, Hallett W, Welniak LA, Sun K, Redelman D, Blazar BR, Levy RB, Murphy WJ. Suppression of natural killer cell-mediated bone marrow cell rejection by CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA. 2006;103:5460–5.Google Scholar
  163. 163.
    Suck G, Branch DR, Smyth MJ, Miller RG, Vergidis J, Fahim S, Keating A. KHYG-1, a model for the study of enhanced natural killer cell cytotoxicity. Exp Hematol. 2005;33:1160–71.PubMedGoogle Scholar
  164. 164.
    Suck G. Novel approaches using natural killer cells in cancer therapy. Semin Cancer Biol. 2006;16:412–8.PubMedGoogle Scholar
  165. 165.
    Uherek C, Tonn T, Uherek B, Becker S, Schnierle B, Klingemann HG, Wels W. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood 2002;100:1265–73.PubMedGoogle Scholar
  166. 166.
    Jiang S, Camara N, Lombardi G, Lechler RI. Induction of allopeptide-specific human CD4+ CD25+ regulatory T cells ex vivo. Blood 2003;102:2180–6.PubMedGoogle Scholar
  167. 167.
    Seddiki N, Santner-Nanan B, Martinson J, Zaunders J, Sasson S, Landay A, Solomon M, Selby W, Alexander SI, Nanan R, Kelleher A, Fazekas de St Groth B. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693–1700.PubMedGoogle Scholar
  168. 168.
    Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS. CD4+ CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. [see comment]. Nat Med. 2003;9:1144–50.PubMedGoogle Scholar
  169. 169.
    Hoffmann P, Boeld TJ, Eder R, Albrecht J, Doser K, Piseshka B, Dada A, Niemand C, Assenmacher M, Orso E, Andreesen R, Holler E, Edinger M. Isolation of CD4+ CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant. 2006;12:267–74.PubMedGoogle Scholar
  170. 170.
    Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+ CD25+ FoxP3+ regulatory T cells. Blood 2005;105:4743–8.PubMedGoogle Scholar
  171. 171.
    Keever-Taylor CA, Browning MB, Johnson BD, Truitt RL, Bredeson CN, Behn B, Tsao A. Rapamycin enriches for CD4(+) CD25(+) CD27(+) Foxp3(+) regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis. Cytotherapy 2007;9:144–57.PubMedGoogle Scholar
  172. 172.
    Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007;7:585–98.PubMedGoogle Scholar
  173. 173.
    Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–42.PubMedGoogle Scholar
  174. 174.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.PubMedGoogle Scholar
  175. 175.
    Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, Deans RJ, Krause DS, Keating A. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 2005;7:393–5.PubMedGoogle Scholar
  176. 176.
    Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. J Cell Physiol. 1998;176:57–66.PubMedGoogle Scholar
  177. 177.
    Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003;57:11–20.PubMedGoogle Scholar
  178. 178.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815–22.PubMedGoogle Scholar
  179. 179.
    Maitra B, Szekely E, Gjini K, Laughlin MJ, Dennis J, Haynesworth SE, Koc ON. Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant. 2004;33:597–604.PubMedGoogle Scholar
  180. 180.
    Noort WA, Kruisselbrink AB, in’t Anker PS, Kruger M, van Bezooijen RL, de Paus RA, Heemskerk MH, Lowik CW, Falkenburg JH, Willemze R, Fibbe WE. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol. 2002;30:870–8.PubMedGoogle Scholar
  181. 181.
    Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, Lazarus HM. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol. 2000;18:307–16.PubMedGoogle Scholar
  182. 182.
    Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004;363:1439–41.PubMedGoogle Scholar
  183. 183.
    Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006;81:1390–7.PubMedGoogle Scholar
  184. 184.
    Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT, Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW, Gerson SL, Laughlin MJ, Loberiza FR Jr, Moseley AB, Bacigalupo A. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005;11:389–98.PubMedGoogle Scholar
  185. 185.
    Farag SS, Fehniger TA, Ruggeri L, Velardi A, Caligiuri MA. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood 2002;100:1935–47.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • David L. Porter
    • 1
    Email author
  • Elizabeth O. Hexner
  • Sarah Cooley
  • Jeffrey S. Miller
  1. 1.Division of Hematology-OncologyUniversity of Pennsylvania Medical CenterPhiladelphiaUSA

Personalised recommendations