Summary
Graft-versus-host disease (GVHD) remains the major problem to be overcome in transplantation of allogeneic haemopoietic stem cells. Using immunosuppressive prophylaxis with cyclosporin and methotrexate, moderate to severe acute GVHD develops in approximately 45% of transplant recipients with an HLA-identical sibling donor and in >75% of patients from unrelated HLA-identical or partially matched related donors.
The pathophysiology of GVHD is complex and still incompletely described. Experimental and clinical data indicate that GVHD is largely mediated by immunocompetent T cells in the donor stem cell graft which are reactive against recipient (host) tissues. Depletion of these immunocompetent T cells from the stem cell graft offers a way to effectively prevent GVHD.
The first section of this review describes the technical principles of different methods of T cell depletion. The advantages, limitations and level of T cell depletion achievable by physical methods or by positive and negative immunoselection procedures using monoclonal antibodies are comprehensively discussed. A short section concentrates on technical problems in the enumeration of T cells in the context of depletion efficiency. In the section on clinical studies, the focus is on the efficacy of different T cell depletion methods in avoiding GVHD in different clinical settings. The various methods are compared in transplantation from HLA-identical and nonidentical siblings or matched unrelated donors.
The major drawbacks of T cell depletion are discussed in detail. Failure of engraftment and graft rejection is a more frequent problem following T cell-depleted transplants, particularly with HLA nonidentical donor-recipient pairs. An increase in leukaemic relapse rate is seen in certain haematological malignancies, especially in chronic myeloid leukaemia. Delayed recovery of anti-infectious immunity occurs, leading to an increased incidence of cytomegalovirus and Epstein-Barr virus related problems.
The aim of this review is not only to give an overview of published studies but also to review strategies to circumvent the drawbacks of TCD. Consequently, we attempt to describe the potential role of cells removed by different depletion methods in graft protection, anti-infectious immunity and graft-versus-leukaemia reactivity. Finally, the possibility of recovering all components of the original graft and readministering them in controlled amounts and at controlled times is discussed. This strategy of ‘balanced component therapy’ may allow the combination of a low rate and severity of GVHD without the disadvantages of T cell depletion.
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References
Korngold B, Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T-cells from marrow [abstract]. J Exp Med 1978; 148: 1687–98
Apperley JF, Jones L, Hale G, et al. Bone marrow transplantation for patients with chronic myeloid leukaemia: T-cell depletion with Campath-1 reduces the incidence of graft versus-host disease but may increase the risk of leukaemic relapse. Bone Marrow Transplant 1986; 1: 53–66
Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–30
Anasetti C, Howe C, Petersdorf EW, et al. Marrow transplants from HLA matched unrelated donors: an NMDP update and the Seattle experience. Bone Marrow Transplant 1994; 13: 693–5
Oudshoorn M, Van Leeuwen A, v.d. Zanden HG, et al. Bone marrow donors worldwide: a successful exercise in international cooperation. Bone Marrow Transplant 1994; 14: 38
Schmitz N, Dreger P, Suttorp M, et al. Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 1995; 85: 1666–72
Link H, Arseniev L, Bähre O, et al. Transplantation of allogeneic CD34+ blood cells. Blood 1996; 87: 4903–9
Finke J, Brugger W, Bertz H, et al. Allogeneic transplantation of positively selected peripheral blood CD34+ progenitor cells from matched related donors. Bone Marrow Transplant 1996; 18: 1081–6
Kolb HT, Mittermuller J, Clemm C, et al. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow fransplant patients. Blood 1990; 76: 2462–5
Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 1995; 86: 2041–50
Lowenberg B, Wagemaker G, van Bekkum DW, et al. Graft-versus-host disease following transplantation of ‘one log’ versus ‘two log’ T-lymphocyte-depleted bone marrow from HLA-identical donors. Bone Marrow Transplant 1986; 1: 133–40
Reisner Y, Kirkpatrick D, Dupont B, et al. Transplantation for acute leukaemia with HLA-A and B nonidentical parental marrow cells fractionated with soybean agglutinin and sheep red blood cells. Lancet 1981; II: 327–31
Reisner Y, Kapoor N, Kirkpatrick D, 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
Frame JN, Collins NH, Cartagena T, et al. T cell depletion of human bone marrow. Comparison of Campath-1 plus complement, anti-T cell ricin A chain immunotoxin, and soybean agglutinin alone or in combination with sheep erythrocytes or immunomagnetic beads. Transplantation 1989; 47: 984–8
Aversa F, Tabilio A, Terenzi A, et al. Successful engraftment of T-cell-depleted haploidentical ‘three-loci’ incompatible transplants 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
Plas A, de Witte T, Wessels H, et al. A new multichamber counterflow centrifugation rotor with high-separation capacity and versatile potentials. Exp Hematol 1988; 16: 355–9
Wagner JE, Donnenberg AD, Noga SJ, et al. Lymphocyte depletion of donor bone marrow by counterflow centrifugal elutriation: results of a phase I clinical trial. Blood 1988; 72: 1168–76
Schattenberg A, de Witte T, Preijers F, et al. Allogeneic bone marrow transplantation for leukemia with marrow grafts depleted of lymphocytes by counterflow centrifugation. Blood 1990; 75: 1356–63
Hale G, Cobbold S, Waldmann H. T cell depletion with CAMPATH-1 in allogeneic bone marrow transplantation. Transplantation 1988; 45: 753–9
Waldmann H, Polliak A, Hale G, et al. Elimination of graft-versus-host disease by in-vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1). Lancet 1984; II: 483–6
Hale G, Waldmann H. Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases. Bone Marrow Transplant 1994; 13: 597–611
Jansen J, Hanks S, Akard L, et al. Immunomagnetic CD8 depletion. Prog Clin Biol Res 1994; 389: 551–6
Siena S, Villa S, Bonadonna G, et al. Specific ex-vivo depletion of human bone marrow T lymphocytes by an anti-pan-T cell (CD5) ricin A-chain immunotoxin. Transplantation 1987; 43: 421–6
Uckun FM, Myers DE, Ledbetter JA, et al. Cell-type-specific cytotoxicity of anti-CD4 and anti-CD8 ricin immunotoxins against human alloreactive T-cell clones. Blood 1989; 74: 2445–54
Racadot E, Herve P, Beaujean F, et al. Prevention of graft-versus-host disease in HLA-matched bone marrow transplantation for malignant diseases: a multicentric study of 62 patients using 3-pan-T monoclonal antibodies and rabbit complement. J Clin Oncol 1987; 5: 426–35
Urbano-Ispizua A, Rozman C, Martinez C, et al. Rapid engraftment without significant graft-versus-host disease after allogeneic transplantation of CD34+ selected cells from peripheral blood. Blood 1997; 85: 3967–73
Hale G, Bright S, Chumbley G, et al. Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 1983; 62: 873–82
Jacobs P, Wood L, Fullard L, et al. T cell depletion by exposure to Campath-1G in vitro prevents graft-versus-host disease. Bone Marrow Transplant 1994; 13: 763–9
Finke J, Brugger W, Bertz H, et al. Allogeneic transplantation of positively selected peripheral blood CD34+ progenitor cells from matched related donors. Bone Marrow Transplant 1996; 18: 1081–6
Bensinger W, Buckner CD, Shannon-Dorcy K, et al. Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy. Blood 1996; 88: 4132–8
Dreger P, Viehmann K, Steinmann J, et al. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: comparison of T cell depletion strategies using different CD34+ selection systems or CAMPATH-1. Exp Hematol 1995; 23: 147–54
Bensinger W, Rowley S, Lilleby K, et al. Reduction in graft versus host disease (GvHD) after transplantation of CD34 selected, allogeneic peripheral blood stem cells (PBSC) in older patients with advanced hematological malignancies [abstract]. Blood 1997; 88: 421
Link H, Arseniev L, Bähre O, et al. Combined transplantation of allogeneic bone marrow and blood hematopoietic progenitor cells. Blood 1995; 86: 2500–8
Martin PJ, Hansen JA. Quantitative assays for detection of residual T cells of T-depleted human marrow. Blood 1985; 65: 1134–40
Irle C, Kaestli M, Aapro M, et al. Quantity and nature of residual bone marrow T cells after treatment of the marrow with Campath-1. Exp Hematol 1987; 15: 163–70
Atkinson K, Farrelly H, Cooley M, et al. Human marrow T cell dose correlates with severity of subsequent acute graft-versus-host disease. Bone Marrow Transplant 1987; 2: 51–7
Kernan NA, Flomenberg N, Collins NH, et al. Quantitation of T lymphocytes in human bone marrow by a limiting dilution assay. Transplantation 1985; 40: 317–22
Rozans MK, Smith BR, Emerson S, et al. Functional assessment of T cell depletion from bone marrow prior to therapeutic transplantation using limiting dilution culture methods. Transplantation 1986; 42: 380–7
Kernan NA, Collins NH, Juliano L, et al. Clonable T lymphocytes in T cell-depleted bone marrow transplants correlate with development of graft-v-host disease. Blood 1986; 68: 770–3
Theobald M. Predicting graft-versus-host disease. Curr Opin Immunol 1995; 7: 649–55
Bunjes D, Theobald M, Nierle T, et al. Presence of host-specific interleukin 2-secreting T helper cell precursors correlates closely with active primary and secondary chronic graft-versus-host disease. Bone Marrow Transplant 1995; 15: 727–32
Antin JH, Bierer BE, Smith BR, et al. Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies. Blood 1991; 78: 2139–49
Reisner Y, Martelli MF. Bone marrow transplantation across HLA barriers by increasing the number of transplanted cells. Immunol Today 1995; 16: 437–40
Verdonck LF, Dekker AW, de Gast GC, et al. Allogeneic bone marrow transplantation with a fixed low number of T cells in the marrow graft. Blood 1994; 83: 3090–6
Pan L, Delmonte Jr 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: 4422–9
Schattenberg A, de Witte T, Salden M, et al. Mixed hematopoietic chimerism after allogeneic transplantation with lymphocyte-depleted bone marrow is not associated with a higher incidence of relapse. Blood 1989; 73: 1367–72
Roux E, Abdi K, Speiser D, et al. Characterization of mixed chimerism in patients with chronic myeloid leukemia transplanted with T-cell-depleted bone marrow: involvement of different hematologic lineages before and after relapse. Blood 1993; 81: 243–8
Roux E, Helg C, Chapius B, et al. Mixed chimerism after bone marrow transplantation and the risk of relapse [letter]. Blood 1994; 84: 4385–6
Hertenstein B, Hampl W, Bunjes D, et al. In vivo/ex vivo T cell depletion for GVHD prophylaxis influences onset and course of active cytomegalovirus infection and disease after BMT. Bone Marrow Transplant 1995; 15: 387–93
Shapiro RS, McClain K, Frizzera G, et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 1988; 71: 1234–43
Lucas KG, Small TN, Heller G, et al. The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation. Blood 1996; 87: 2594–603
Prentice HG, Blacklock HA, Janossy G, et al. Use of anti-T-cell monoclonal antibody OKT3 to prevent acute graft-versus-host disease in allogenic bone-marrow transplantation for acute leukaemia. Lancet 1982; II: 700–3
Prentice HG, Blacklock HA, Janossy G, et al. Depletion of T lymphocytes in donor marrow prevents significant graft-versus-host disease in matched allogeneic leukaemic marrow transplant recipients. Lancet 1984; I: 472–6
Martin PJ, Hansen JA, Buckner CD, et al. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 1985; 66: 664–72
Mitsuyasu RT, Champlin RE, Gale RP, et al. Treatment of donor bone marrow with monoclonal anti-T-cell antibody and complement for the prevention of graft-versus-host disease. A prospective, randomized, double-blind trial. Ann Intern Med 1986; 105: 20–6
Filipovich AH, Vallera DA, Youle RJ, et al. Graft-versus-host disease prevention in allogeneic bone marrow transplantation from histocompatible siblings. A pilot study using immunotoxins for T cell depletion of donor bone marrow. Transplantation 1987; 44: 62–9
Maraninchi D, Gluckman E, Blaise D, et al. Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet 1987; II: 175–8
Hervé P, Cahn JY, Flesch M, et al. Successful graft-versus-host disease prevention without graft failure in 32 HLA-identical allogeneic bone marrow transplantations with marrow depleted of T cells by monoclonal antibodies and complement. Blood 1987; 69: 388–93
Laurent G, Bouloux C. Prevention of graft-versus-host disease by using immunotoxins. Prog Clin Biol Res 1992; 377: 129–36
Wagner JE, Santos GW, Noga SJ, et al. Bone marrow graft engineering by counterflow centrifugal elutriation: results of a phase I–II clinical trial. Blood 1990; 75: 1370–7
Young JW, Papadopoulos EB, Cunningham I, et al. T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission. Blood 1992; 79: 3380–7
Hale G, Waldmann H. Recent results using Campath-1 antibodies to control G vs HD and graft rejection [abstract]. Bone Marrow Transplant 1996; 17: 305–8
Korngold R. Biology of graft-vs-host disease. Am J Pediatr Hematol Oncol 1993; 15: 18–27
Champlin R, Giralt S, Przepiorka D, et al. Selective depletion of CD8-positive T-lymphocytes for allogeneic bone marrow transplantation: engraftment, graft-versus-host disease and graft-versus leukemia. Prog Clin Biol Res 1992; 377: 385–94
Ringdén O, Remberger M, Aschan J, et al. Long-term follow-up of a randomized trial comparing T cell depletion with a combination of methotrexate and cyclosporine in adult leukemic marrow transplant recipients. Transplantation 1994; 58: 887–91
Soiffer RJ, Murray C, Mauch P, et al. Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow. J Clin Oncol 1992; 10: 1191–200
Soiffer RJ, Fairclough D, Robertson M, et al. CD6-depleted allogeneic bone marrow transplantation for acute leukemia in first complete remission. Blood 1997; 89: 3039–47
Nimer SD, Giorgi J, Gajewski JL, et al. Selective depletion of CD8+ cells for prevention of graft-versus-host disease after bone marrow transplantation. A randomized controlled trial. Transplantation 1994; 57: 82–7
Clark RE, Pender N. Transplantation of T-lymphocyte depleted marrow with an addback of T cells. Hematol Oncol 1995; 13: 219–24
Jacobs P. Allogeneic bone marrow transplantation with a fixed low number of T-cells in the marrow graft [letter]. Blood 1994; 84: 3597–8
Champlin R. Optimizing the composition of bone marrow for allogenic transplantation. J Hematother 1995; 4: 53–60
Giralt S, Hester J, Huh Y, et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995; 86: 4337–43
Fischer A, Friedrich W, Fasth A, et al. Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi’s anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report. Blood 1991; 77: 249–56
Ganem G, Kuentz M, Beaujean F, et al. Additional total-lymphoid irradiation in preventing graft failure of T-cell-depleted bone marrow transplantation from HLA-identical siblings. Results of a prospective randomized study. Transplantation 1988; 45: 244–8
Cahn JY, Herve P, Flesch M, et al. Marrow transplantation from HLA non-identical family donors for the treatment of leukaemia: a pilot study of 15 patients using additional immunosuppression and T-cell depletion. Br J Haematol 1988; 69: 345–9
Hale G, Phillips JM. Clinical trials with CAMPATH-I and other monoclonal antibodies. Biochem Soc Trans 1995; 23: 1057–63
Wiesneth M, Hertenstein B, Bunjes D, et al. T-cell depletion versus methotrexate as GvHD-prophylaxis in allogeneic bone marrow transplantation for leukaemia. Eur J Haematol 1988; 41: 243–9
Hobbs JR, Hugh Jones K, Shaw PJ, et al. Engraftment rates related to busulphan and cyclophosphamide dosages for displacement bone marrow transplants in fifty children. Bone Marrow Transplant 1986; 1: 201–8
Bunjes D, Hertenstein B, Wiesneth M, et al. In vivo/ex vivo T cell depletion reduces the morbidity of allogeneic bone marrow transplantation in patients with acute leukaemias in first remission without increasing the risk of treatment failure: comparison with cyclosporin/methotrexate. Bone Marrow Transplant 1995; 15: 563–8
Bunjes D, Theobald M, Hertenstein B, et al. Successful therapy with donor buffy coat transfusions in patients with relapsed chronic myeloid leukemia after bone marrow transplantation is associated with high frequencies of host-reactive interleukin 2-secreting T helper cells. Bone Marrow Transplant 1995; 15: 713–9
Naparstek E, Or R, Nagler A, et al. T-cell-depleted allogeneic bone marrow transplantation for acute leukaemia using Campath-1 antibodies and post-transplant administration of donor’s peripheral blood lymphocytes for prevention of relapse. Br J Haematol 1995; 89: 506–15
Mackinnon S, Papadopoulos EB, Carabasi MH, et al. Adoptive immunotherapy using donor leukocytes following bone marrow transplantation for chronic myeloid leukemia: is T cell dose important in determining biological response? Bone Marrow Transplant 1995; 15: 591–4
Mackinnon S, Papadopoulos EB, Carabasi MH, et al. Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graftversus-host disease. Blood 1995; 86: 1261–8
Champlin R, Gajewski J, Feig S, et al. Selective depletion of CD8 positive T-lymphocytes for prevention of graft-versus-host disease following allogeneic bone marrow transplantation. Transplant Proc 1989; 21: 2947–8
Tiberghien P, Reynolds CW, Keller J, et al. Ganciclovir treatment of herpes simplex thymidine kinase-transduced primary T lymphocytes: an approach for specific in vivo donor T-cell depletion after bone marrow transplantation? Blood 1994; 84: 1333–41
Marmont AM. Alloimmune effects of bone marrow transplantation for leukaemia on the leukaemic diseases. Bone Marrow Transplant 1991; 7Suppl. 2: 2–3
Henslee-Downey PJ, Parrish RS, Macdonald JS, et al. Combined in vitro and in vivo T lymphocyte depletion for the control of graft-versus-host disease following haploidentical marrow transplant. Transplantation 1996; 61: 738–45
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: 485–94
Drobyski WR, Ash RC, Casper JT, et al. Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia. Blood 1994; 83: 1980–7
Spencer A, Szydlo RM, Brookes PA, et al. Bone marrow transplantation for chronic myeloid leukemia with volunteer unrelated donors using ex vivo or in vivo T-cell depletion: major prognostic impact of HLA class I identity between donor and recipient. Blood 1995; 86: 3590–7
Oakhill A, Pamphilon DH, Potter MN, et al. Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete revision. Br J Haematol 1996; 94: 574–8
Cavazzana-Calvo M, Bordigoni P, Michel G, et al. A phase II trial of partially incompatible bone marrow transplantation for high-risk acute lymphoblastic leukaemia in children: prevention of graft rejection with anti-LFA-1 and anti CD2 antibodies. B J Haematol 1996; 93: 131–8
Cullis JO, Szydlo RM, Cross NC, et al. Matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia in chronic phase: comparison of ex vivo and in vivo T-cell depletion. Bone Marrow Transplant 1993; 11Suppl. 1: 107–11
Albi N, Ruggeri L, Aversa F, et al. Natural killer (NK)-cell function and antileukemic activity of a large population of CD3+/CD8+ T cells expressing NK receptors for major histocompatibility complex class I after ‘three-loci’ HLA-incompatible bone marrow transplantation. Blood 1996; 87: 3993–4000
Hessner MJ, Endean DJ, Casper JT, et al. Use of unrelated marrow grafts compensates for reduced graft-versus-leukemia reactivity after T-cell-depleted allogeneic marrow transplantation for chronic myelogenous leukemia. Blood 1995; 86: 3987–96
Devergie A, Labopin M, Apperley J, et al. European results of 357 matched unrelated donor (MUD) transplants for chronic myeloid leukemia (CML). Impact of HLAD subtypes analyses [abstract]. Blood 1994; 84: 537
Korbling M, Huh YO, Durett A, et al. Allogeneic blood stem cell transplantation: peripheralization and yield of donor-derived primitive hematopoietic progenitor cells (CD34+ Thy-1dim ) and lymphoid subsets, and possible predictors of engraftment and graft-versus-host disease. Blood 1995; 86: 2842–8
Bensinger W, Buckner CD, Shannon-Dorcy K, et al. Transplantation of allogeneic CD34+ peripheral blood stem cells in patients with advanced hematologic malignancy. Blood 1996; 88: 4132–8
Hertenstein B, Arseniev L, Novotny J, et al. Transplantation of allogeneic CD34+ blood cells additionally T-cell depleted with Campath-1H [abstract]. Bone Marrow Transplant 1997; 19: S151
Stockschläder M, Hassan HT, Zeller W, et al. Allogeneic transplantation with CD34+ selected cells. Leuk Lymphoma 1997; 25: 145–51
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Hertenstein, B., Arseniev, L., Novotny, J. et al. A Comparative Review of Methods for T Cell Depletion in the Prophylaxis of Graft-versus-Host Disease. BioDrugs 9, 105–123 (1998). https://doi.org/10.2165/00063030-199809020-00003
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DOI: https://doi.org/10.2165/00063030-199809020-00003