Seminars in Oncology
Volume 31, Issue 1 , Pages 56-67 , February 2004

Immunoablative reduced-intensity stem cell transplantation: potential role of donor Th2 and Tc2 cells

  • Daniel H Fowler

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Daniel H. Fowler, MD, National Institutes of Health, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bldg 10, Room 12N226, Bethesda, MD, 20892, USA
    • National Institutes of Health, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  • ,
  • Michael R Bishop

      Affiliations

    • National Institutes of Health, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
  • ,
  • Ronald E Gress

      Affiliations

    • National Institutes of Health, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

References 

  1. Klingemann HG, Shepherd JD, Reece DE, et al.  Regimen-related acute toxicities (Pathophysiology, risk factors, clinical evaluation, and preventative strategies). Bone Marrow Transplant. 1994;14(suppl 4):S14–S18
  2. Reisner Y, Ben-Bassat I, Douer D, et al.  Demonstration of clonable alloreactive host T-cells in a primate model for bone marrow transplantation. Proc Natl Acad Sci USA. 1986;83:4012–4015
  3. Vallera DA, Taylor PA, Sprent J, et al.  The role of host T-cell subsets in bone marrow rejection directed to isolated major histocompatibility complex class I versus class II differences of bm1 and bm12 mutant mice. Transplantation. 1994;57:249–256
  4. Martin PJ, Hansen JA, Torok-Storb B, et al.  Graft failure in patients receiving T-cell-depleted HLA-identical allogeneic marrow transplants. Bone Marrow Transplant. 1988;3:445–456
  5. Gale RP, Reisner Y. Graft rejection and graft-versus-host disease (Mirror images). Lancet. 1986;1:1468–1470
  6. Martin PJ. Determinants of engraftment after allogeneic marrow transplantation. Blood. 1992;79:1647–1650
  7. Khouri IF, Keating M, Korbling M, et al.  Transplant-lite (Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies). J Clin Oncol. 1998;16:2817–2824
  8. Spitzer TR, McAfee S, Sackstein R, et al.  Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant. 2000;6:309–320
  9. McSweeney PA, Niederwiesser D, Shizuru JA, et al.  Hematopoietic cell transplantation in older patients with hematologic malignancies (Replacing high-dose cytotoxic therapy with graft-versus-tumor effects). Blood. 2001;97:3390–3400
  10. Hakim FT, Cepeda R, Kaimei S, et al.  Constraints on CD4 recovery postchemotherapy in adults (Thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells). Blood. 1997;90:3789–3798
  11. Sykes M. Mixed chimerism and transplant tolerance. Immunity. 2001;14:417–424
  12. Blazar BR, Lees CJ, Martin PJ, et al.  Host T-cells resist graft-versus-host disease mediated by donor leukocyte infusions. J Immunol. 2000;165:4901–4909
  13. Childs R, Clave E, Contentin N, et al.  Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation (Full donor T-cell chimerism precedes alloimmune responses). Blood. 1999;94:3234–3241
  14. Korngold R, Sprent J. Graft-versus-host disease in experimental allogeneic bone marrow transplantation. Proc Soc Exp Biol Med. 1991;197:12–18
  15. Ash RC, Casper JT, Chitambar CR, et al.  Successful allogeneic transplantation of T-cell-depleted bone marrow from closely HLA-matched unrelated donors. N Engl J Med. 1990;322:485–494
  16. Petersdorf EW, Smith AG, Mickelson EM, et al.  Influence of HLA-DPB1 disparity on the development of acute graft-versus-host disease following unrelated donor marrow transplantation. Transplant Proc. 1993;25:1230–1231
  17. Tseng LH, Lin MT, Hansen JA, et al.  Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation. Blood. 1999;94:2911–2914
  18. Cavet J, Middleton PG, Segall M, et al.  Recipient tumor necrosis factor-alpha and interleukin-10 gene polymorphisms associate with early mortality and acute graft-versus-host disease severity in HLA-matched sibling bone marrow transplants. Blood. 1999;94:3941–3946
  19. Shlomchik WD, Couzens MS, Tang CB, et al.  Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science. 1999;285:412–415
  20. Hill GR, Crawford JM, Cooke KR, et al.  Total body irradiation and acute graft-versus-host disease (The role of gastrointestinal damage and inflammatory cytokines). Blood. 1997;90:3204–3213
  21. Hill GR, Teshima T, Gerbitz A, et al.  Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia. J Clin Invest. 1999;104:459–467
  22. Hill GR, Ferrara JL. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease (Rationale for the use of cytokine shields in allogeneic bone marrow transplantation). Blood. 2000;95:2754–2759
  23. Nestel FP, Price KS, Seemayer TA, et al.  Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med. 1992;175:405–413
  24. Barrett J, Childs R. Non-myeloablative stem cell transplants. Br J Haematol. 2000;111:6–17
  25. Khouri IF, Saliba RM, Giralt SA, et al.  Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma (Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality). Blood. 2001;98:3595–3599
  26. Slavin S, Nagler A, Naparstek E, et al.  Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998;91:756–763
  27. Giralt S, Thall PF, Khouri I, et al.  Melphalan and purine analog-containing preparative regimens (Reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation). Blood. 2001;97:631–637
  28. Wasch R, Reisser S, Hahn J, et al.  Rapid achievement of complete donor chimerism and low regimen-related toxicity after reduced conditioning with fludarabine, carmustine, melphalan and allogeneic transplantation. Bone Marrow Transplant. 2000;26:243–250
  29. Mapara MY, Kim YM, Wang SP, et al.  Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras (A critical role for host antigen-presenting cells). Blood. 2002;100:1903–1909
  30. Sykes M, Preffer F, McAfee S, et al.  Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Blood. 1998;91:4045–4050
  31. Mackinnon S, Barnett L, Heller G, et al.  Minimal residual disease is more common in patients who have mixed T-cell chimerism after bone marrow transplantation for chronic myelogenous leukemia. Blood. 1994;83:3409–3416
  32. Wasch R, Bertz H, Kunzmann R, et al.  Incidence of mixed chimaerism and clinical outcome in 101 patients after myeloablative conditioning regimens and allogeneic stem cell transplantation. Br J Haematol. 2000;109:743–750
  33. 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;343:750–758
  34. Robinson SP, Goldstone AH, Mackinnon S, et al.  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;100:4310–4316
  35. Petrus MJ, Williams JF, Eckhaus MA, et al.  An immunoablative regimen of fludarabine and cyclophosphamide prevents fully MHC-mismatched murine marrow graft rejection independent of GVHD. Biol Blood Marrow Transplant. 2000;6:182–189
  36. Bishop MR, Hou J, Wilson WH, et al.  Establishment of early donor engraftment after reduced-intensity allogeneic hematopoietic stem cell transplantation to potentiate the graft-versus-lymphoma effect against refractory lymphomas. Biol Blood Marrow Transplant. 2003;9:162–169
  37. Gutierrez M, Chabner BA, Pearson D, et al.  Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas (An 8-year follow-up study of EPOCH). J Clin Oncol. 2000;18:3633–3642
  38. Flinn IW, Byrd JC, Morrison C, et al.  Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood. 2000;96:71–75
  39. Bellosillo B, Colomer D, Pons G, et al.  Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells. Br J Haematol. 1998;100:142–146
  40. O’Brien S, Kantarjian H, Beran M, et al.  Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993;82:1695–1700
  41. Przepiorka D, Smith TL, Folloder J, et al.  Controlled trial of filgrastim for acceleration of neutrophil recovery after allogeneic blood stem cell transplantation from human leukocyte antigen-matched related donors. Blood. 2001;97:3405–3410
  42. Frankel W, Chan A, Corringham RE, et al.  Detection of chimerism and early engraftment after allogeneic peripheral blood stem cell or bone marrow transplantation by short tandem repeats. Am J Hematol. 1996;52:281–287
  43. Carella AM, Cavaliere M, Lerma E, et al.  Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol. 2000;18:3918–3924
  44. Mosmann TR, Cherwinski H, Bond MW, et al.  Two types of murine helper T-cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–2357
  45. Loza MJ, Perussia B. Final steps of natural killer cell maturation (a model for type 1-type 2 differentiation?). Nat Immunol. 2001;2:917–924
  46. Kalinski P, Hilkens CM, Snijders A, et al.  IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol. 1997;159:28–35
  47. Carter LL, Dutton RW. Relative perforin- and Fas-mediated lysis in T1 and T2 CD8 effector populations. J Immunol. 1995;155:1028–1031
  48. Le Gros G, Ben-Sasson SZ, Seder R, et al.  Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro (IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells). J Exp Med. 1990;172:921–929
  49. Yoshimoto T, Bendelac A, Watson C, et al.  Role of NK1.1+ T-cells in a TH2 response and in immunoglobulin E production. Science. 1995;270:1845–1847
  50. Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T-cell responses (The alternative approaches). Annu Rev Immunol. 1997;15:297–322
  51. Rissoan MC, Soumelis V, Kadowaki N, et al.  Reciprocal control of T helper cell and dendritic cell differentiation. Science. 1999;283:1183–1186
  52. Faries MB, Bedrosian I, Xu S, et al.  Calcium signaling inhibits interleukin-12 production and activates CD83(+) dendritic cells that induce Th2 cell development. Blood. 2001;98:2489–2497
  53. 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;2:271–279
  54. Abhyankar S, Gilliland DG, Ferrara JL. Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens. Transplantation. 1993;56:1518–1523
  55. Via CS, Finkelman FD. Critical role of interleukin-2 in the development of acute graft-versus-host disease. Int Immunol. 1993;5:565–572
  56. Batchelor JR, Schwarer AP, Yin ZJ, et al.  Helper T-lymphocyte precursor frequencies predict risks of graft-versus-host disease in bone marrow transplantation. Transplant Proc. 1993;25:1237–1238
  57. Lee BO, Haynes L, Eaton SM, et al.  The biological outcome of CD40 signaling is dependent on the duration of CD40 ligand expression (Reciprocal regulation by interleukin (IL)-4 and IL-12). J Exp Med. 2002;196:693–704
  58. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, et al.  Blockade of CD40 ligand-CD40 interaction impairs CD4+ T-cell-mediated alloreactivity by inhibiting mature donor T-cell expansion and function after bone marrow transplantation. J Immunol. 1997;158:29–39
  59. Via CS, Nguyen P, Shustov A, et al.  A major role for the Fas pathway in acute graft-versus-host disease. J Immunol. 1996;157:5387–5393
  60. Schmaltz C, Alpdogan O, Horndasch KJ, et al.  Differential use of Fas ligand and perforin cytotoxic pathways by donor T-cells in graft-versus-host disease and graft-versus-leukemia effect. Blood. 2001;97:2886–2895
  61. Lin T, Brunner T, Tietz B, et al.  Fas ligand- mediated killing by intestinal intraepithelial lymphocytes. Participation in intestinal graft-versus-host disease. J Clin Invest. 1998;101:570–577
  62. Kataoka Y, Iwasaki T, Kuroiwa T, et al.  The role of donor T-cells for target organ injuries in acute and chronic graft-versus-host disease. Immunology. 2001;103:310–318
  63. Teshima T, Ordemann R, Reddy P, et al.  Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med. 2002;8:575–581
  64. Cox GW, Melillo G, Chattopadhyay U, et al.  Tumor necrosis factor-alpha-dependent production of reactive nitrogen intermediates mediates IFN-gamma plus IL-2-induced murine macrophage tumoricidal activity. J Immunol. 1992;149:3290–3296
  65. Sher A, Gazzinelli RT, Oswald IP, et al.  Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992;127:183–204
  66. Fowler DH, Kurasawa K, Husebekk A, et al.  Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment. J Immunol. 1994;152:1004–1013
  67. Fowler DH, Kurasawa K, Smith R, et al.  Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood. 1994;84:3540–3549
  68. Krenger W, Snyder KM, Byon JC, et al.  Polarized type 2 alloreactive CD4+ and CD8+ donor T-cells fail to induce experimental acute graft-versus-host disease. J Immunol. 1995;155:585–593
  69. Fowler DH, Breglio J, Nagel G, 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;2:118–125
  70. Fowler DH, Breglio J, Nagel G, et al.  Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol. 1996;157:4811–4821
  71. Jung U, Foley JE, Erdmann AE, et al.  CD3, CD28 co-stimulated T1 vs. T2 subsets (Differential in vivo allosensitization generates distinct GVT and GVHD effects). Blood. 2003;102:3439–3446
  72. Dobrzanski MJ, Reome JB, Dutton RW. Therapeutic effects of tumor-reactive type 1 and type 2 CD8+ T-cell subpopulations in established pulmonary metastases. J Immunol. 1999;162:6671–6680
  73. Kemp RA, Ronchese F. Tumor-specific Tc1, but not Tc2, cells deliver protective antitumor immunity. J Immunol. 2001;167:6497–6502
  74. Pan L, Delmonte J, Jalonen CK, et al.  Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood. 1995;86:4422–4429
  75. Sloand EM, Kim S, Maciejewski JP, et al.  Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo. Blood. 2000;95:2269–2274
  76. Arpinati M, Green CL, Heimfeld S, et al.  Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood. 2000;95:2484–2490
  77. Levine BL, Bernstein WB, Connors M, et al.  Effects of CD28 costimulation on long-term proliferation of CD4+ T-cells in the absence of exogenous feeder cells. J Immunol. 1997;159:5921–5930
  78. Levine BL, Bernstein WB, Aronson NE, et al.  Adoptive transfer of costimulated CD4+ T-cells induces expansion of peripheral T-cells and decreased CCR5 expression in HIV infection. Nat Med. 2002;8:47–53
  79. Garlie NK, LeFever AV, Siebenlist RE, et al.  T-cells coactivated with immobilized anti-CD3 and anti-CD28 as potential immunotherapy for cancer. J Immunother. 1999;22:336–345
  80. Boise LH, Minn AJ, Noel PJ, et al.  CD28 costimulation can promote T-cell survival by enhancing the expression of Bcl-XL. Immunity. 1995;3:87–98
  81. Okkenhaug K, Wu L, Garza KM, et al.  A point mutation in CD28 distinguishes proliferative signals from survival signals. Nat Immunol. 2001;2:325–332
  82. Brown DR, Green JM, Moskowitz NH, et al.  Limited role of CD28-mediated signals in T helper subset differentiation. J Exp Med. 1996;184:803–810
  83. Fowler DH, Hou J, Foley J, et al.  Phase I clinical trial of donor T-helper Type-2 cells after immunoablative, reduced intensity allogeneic PBSC transplant. Cytotherapy. 2002;4:429–430
  84. Martin PJ. Donor CD8 cells prevent allogeneic marrow graft rejection in mice (Potential implications for marrow transplantation in humans). J Exp Med. 1993;178:703–712
  85. Martin PJ, Rowley SD, Anasetti C, 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;94:2192–2199
  86. Fink PJ, Shimonkevitz RP, Bevan MJ. Veto cells. Annu Rev Immunol. 1988;6:115–137
  87. Hiruma K, Nakamura H, Henkart PA, et al.  Clonal deletion of postthymic T-cells (Veto cells kill precursor cytotoxic T lymphocytes). J Exp Med. 1992;175:863–868
  88. Reich-Zeliger S, Zhao Y, Krauthgamer R, et al.  Anti-third party CD8+ CTLs as potent veto cells (Coexpression of CD8 and FasL is a prerequisite). Immunity. 2000;13:507–515
  89. Spaner D, Raju K, Rabinovich B, et al.  A role for perforin in activation-induced T-cell death in vivo (Increased expansion of allogeneic perforin-deficient T-cells in SCID mice). J Immunol. 1999;162:1192–1199
  90. Chrobak P, Gress RE. Veto activity of activated bone marrow does not require perforin and Fas ligand. Cell Immunol. 2001;208:80–87
  91. George JF, Thomas JM. The molecular mechanisms of veto mediated regulation of alloresponsiveness. J Mol Med. 1999;77:519–526
  92. Bachar-Lustig E, Reich-Zeliger S, Gur H, et al.  Bone marrow transplantation across major genetic barriers (The role of megadose stem cells and nonalloreactive donor anti-third party CTLS). Transplant Proc. 2001;33:2099–2100
  93. Martelli MF, Reisner Y. Haploidentical ‘megadose’ CD34+ cell transplants for patients with acute leukemia. Leukemia. 2002;16:404–405
  94. Nakamura H, Gress RE. Interleukin 2 enhancement of veto suppressor cell function in T-cell-depleted bone marrow in vitro and in vivo. Transplantation. 1990;49:931–937
  95. Bachar-Lustig E, Li HW, Marcus H, et al.  Tolerance induction by megadose stem cell transplants (Synergism between SCA-1+ Lin- cells and nonalloreactive T-cells). Transplant Proc. 1998;30:4007–4008
  96. Martin PJ. Prevention of allogeneic marrow graft rejection by donor T-cells that do not recognize recipient alloantigens (Potential role of a veto mechanism). Blood. 1996;88:962–969
  97. Fowler DH, Whitfield B, Livingston M, et al.  Non-host-reactive donor CD8+ T-cells of Tc2 phenotype potently inhibit marrow graft rejection. Blood. 1998;91:4045–4050
  98. Mavroudis DA, Dermime S, Molldrem J, et al.  Specific depletion of alloreactive T-cells in HLA-identical siblings (A method for separating graft-versus-host and graft-versus-leukaemia reactions). Br J Haematol. 1998;101:565–570
  99. Krenger W, Cooke KR, Crawford JM, et al.  Transplantation of polarized type 2 donor T-cells reduces mortality caused by experimental graft-versus-host disease. Transplantation. 1996;62:1278–1285
  100. Halverson DC, Schwartz GN, Carter C, et al.  In vitro generation of allospecific human CD8+ T-cells of Tc1 and Tc2 phenotype. Blood. 1997;90:2089–2096

PII: S0093-7754(03)00565-7

doi: 10.1053/j.seminoncol.2003.11.003

Seminars in Oncology
Volume 31, Issue 1 , Pages 56-67 , February 2004