[en] BACKGROUND: We have previously shown that CD8 depletion or CD34 selection of peripheral blood stem cells (PBSC) reduced the incidence of acute graft-versus-host disease (GvHD) after nonmyeloablative stem-cell transplantation (NMSCT). In this study, we analyze the effect of CD8 depletion or CD34 selection of the graft on early T-cell reconstitution. METHODS: Nonmyeloablative conditioning regimen consisted in 2 Gy total-body irradiation (TBI) alone, 2 Gy TBI and fludarabine, or cyclophosphamide and fludarabine. Patients 1 to 18 received unmanipulated PBSC, patients 19 to 29 CD8-depleted PBSC, and patients 30 to 35 CD34-selected PBSC. RESULTS: T-cell counts, and particularly CD4+ and CD4CD45RA+ counts, remained low the first 6 months after nonmyeloablative stem-cell transplantation (NMSCT) in all patients. CD34 selection (P<0.0001) but not CD8 depletion of PBSC significantly decreased T-cell chimerism. Donor T-cell count was similar in unmanipulated compared with CD8-depleted PBSC recipients but was significantly lower in CD34-selected PBSC recipients (P=0.0012). T cells of recipient origin remained stable over time in unmanipulated and CD8-depleted PBSC patients but expanded in some CD34-selected PBSC recipients between day 28 and 100 after transplant. Moreover, whereas CD8 depletion only decreased CD8+ counts (P<0.047), CD34 selection reduced CD3+(P<0.001), CD8+(P<0.016), CD4+ (P<0.001), and CD4+CD45RA+ (P<0.001) cell counts. T-cell repertoire was restricted in all patients on day 100 after hematopoietic stem-cell transplantation but was even more limited after CD34 selection (P=0.002). CONCLUSIONS: Despite of the persistence of a significant number of T cells of recipient origin, T-cell counts were low the first 6 months after NMSCT. Moreover, contrary with CD8 depletion of the graft that only affects CD8+ lymphocyte counts, CD34 selection dramatically decreased both CD8 and CD4 counts.
Disciplines :
Hematology
Author, co-author :
Baron, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Schaaf-Lafontaine, Nicole ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie biologique et immuno hématologie
Storb R. Allogeneic hematopoietic stem cell transplantation: yesterday, today, and tomorrow. Exp Hematol 2003; 31: 1.
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.
Baron F, Beguin Y. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic HPC transplantation. Transfusion 2000; 40: 468.
Baron F, Beguin Y. Nonmyeloablative allogeneic hematopoietic stem cell transplantation. J Hematother Stem Cell Res 2002; 11: 243.
McSweeney PA, Storb R. Mixed chimerism: preclinical studies and clinical applications. Biol Blood Marrow Transplant 1999; 5: 192.
McSweeney PA, Niederwieser D, Shizuru J, 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.
Niederwieser D, Maris M, Shizuru JA, et al. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 2003; 101: 1620.
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 response. Blood 1999; 94: 3234.
Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98: 3192.
Nimer SD, Giorgi J, Gajewski JL, et al. Selective depletion of CD8+ cells for prevention of graft-versus-host disease after bone marrow transplantation. Transplantation 1994; 57: 82.
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.
Alyea EP, Weller E, Schlossman R, et al. T-cell-depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect. Blood 2001; 98: 934.
Barrett AJ, Mavroudis D, Tisdale J, et al. T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect. Bone Marrow Transplant 1998; 21: 543.
Baron F, Siquet J, Schaaf-Lafontaine N, et al. Pre-emptive immunotherapy with CD8-depleted donor lymphocytes after CD34-selected allogeneic peripheral blood stem cell transplantation. Haematologica 2002; 87: 78.
Baron F, Baudoux E, Frere P, et al. nonmyeloablative stem cell transplantation with CD8-depleted or CD34-selected peripheral blood stem cells. J Hematother Stem Cell Res 2002; 11: 301.
Baron F, Frere P, Baudoux E, et al. Low incidence of acute graft-versus-host disease after non-myeloablative stem cell transplantation with CD8-depleted peripheral blood stem cells: an update. Haematologica 2003; 88: 820.
Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825.
Margolis J, Vogelsang G. Chronic graft-versus-host disease. J Hematother Stem Cell Res 2000; 9: 339.
Baron F, Turhan AG, Giron-Michel J, et al. Leukemic target susceptibility to natural killer cytotoxicity: relationship with BCR-ABL expression. Blood 2002; 99: 2107.
Genevee C, Diu A, Nierat J, et al. An experimentally validated panel of subfamily-specific oligonucleotide primers (V alpha 1-w29/V beta 1-w24) for the study of human T cell receptor variable V gene segment usage by polymerase chain reaction. Eur J Immunol 1992; 22: 1261.
Wu CJ, Chillemi A, Alyea EP, et al. Reconstitution of T-cell receptor repertoire diversity following T-cell depleted allogeneic bone marrow transplantation is related to hematopoietic chimerism. Blood 2000; 95: 352.
Storek J, Dawson MA, Storer B, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97: 3380.
Roux E, Helg C, Dumont-Girard F, et al. Analysis of T cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T cell depleted and unmanipulated grafts. Blood 1996; 87: 3984.
Junghanss C, Boeckh M, Carter RA, et al. Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002; 99: 1978.
Foster AE, Gottlieb DJ, Sartor M, et al. Cytomegalovirus-specific CD4+ and CD8+ T-cells follow a similar reconstitution pattern after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2002; 8: 501.
Maris MB, Boeckh M, Dawson MA, et al. Immunologic recovery after nonmyeloablative compared to conventional hematopoietic stem cell transplantation (HSCT) using peripheral blood stem cells (PBSC) from HLA identical sibling donors. Blood 2002; 100: 3329.
Busca A, Falda M, Genetta C, et al. Immune reconstitution following allogeneic nonmyeloablative stem cell transplantation (NST). Bone Marrow Transplant 2002; 29(Suppl 2): s155.
Friedman TM, Varadi G, Hopely DD, et al. Nonmyeloablative conditioning allows for more rapid T-cell repertoire reconstitution following allogeneic matched unrelated bone marrow transplantation compared to myeloablative approaches. Biol Blood Marrow Transplant 2001; 7: 656.
Chao NJ, Liu CX, Rooney B, et al. Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells. Biol Blood Marrow Transplant 2002; 8: 249.
