Abstract
Here we investigated the influence of parameters known before hematopoietic stem cell transplantation (HSCT) as well as the relevance of graft-versus-host disease (GvHD) and cytomegalovirus (CMV) reactivation on post transplant lymphocyte reconstitution in 148 patients treated in our institution between 1996 and 2003. Median patient age was 42 (19–68) years, HSCT followed standard high dose (n=91) or reduced-intensity conditioning regimens (n=57) with bone marrow (BM, n=67) or peripheral blood stem cells (PBSC, n=81) from related (n=71) or unrelated (n=77) donors. In the first months, we observed a partially faster reconstitution of CD3+4+, CD3+8+ and CD4+45RA+ T cells in patients following peripheral blood stem cell transplantation when compared to bone marrow transplantation. Prolonged CD3+4+ and CD4+45RA+ lymphopenia was noted after unrelated donor HSCT and GvHD prophylaxis containing anti-T-lymphocyte globulin. Lymphocyte subset counts in patients older than the median age were comparable to those in patients transplanted at a younger age and not influenced by the conditioning regimen. CD3+8+ T cell reconstitution was strongly correlated with CMV reactivation, but not significantly affected by CMV serostatus before HSCT. Incidence or extent of GvHD did not significantly influence lymphocyte reconstitution. Therefore, the source of graft is the most predictive parameter in early lymphocyte reconstitution, but the differences in lymphocyte recovery completely resolved within the first year after HSCT.
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References
Storek J, Espino G, Dawson MA, Storer B, Flowers ME, Maloney DG . Low B cell and monocyte counts on day 80 are associated with high infection rates between day 100 and 365 after allogeneic marrow transplantation. Blood 2000; 96: 3290–3293.
Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R . Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Haematol 1997; 54: 131–138.
Kim DH, Sohn SK, Won DI, Lee NY, Suh JS, Lee KB . Rapid helper T-cell recovery above 200 × 106/l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 37: 1119–1128.
Novitzky N, Davison GM, Hale G, Waldmann H . Immune reconstitution at 6 months following T-cell depleted hematopoietic stem cell transplantation is predictive for treatment outcome. Transplantation 2002; 74: 1551–1559.
Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2100.
Guermonprez P, Valladeau J, Zitvogel L, Thery C, Amigorena S . Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 2002; 20: 621–667.
Damiani D, Stocchi R, Masolini P, Michelutti A, Sperotto A, Geromin A et al. Dendritic cell recovery after autologous stem cell transplantation. Bone Marrow Transplant 2002; 30: 261–266.
Auletta JJ, Lazarus HM . Immune restoration following hematopoietic stem cell transplantation: an evolving target. Bone Marrow Transplant 2005; 35: 835–857.
Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska EM et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 2001; 97: 1458–1466.
Korbling M, Przepiorka D, Huh YO, Engel H, van Besien K, Giralt S et al. Allogeneic blood stem cell transplantation for refractory leukaemia and lymphoma: potential advantage of blood over marrow allografts. Blood 1995; 85: 1659–1665.
Bensinger WI, Clift R, Martin P, Appelbaum FR, Demirer T, Gooley T et al. Allogeneic peripheral blood stem cell transplantation in patients with advanced malignancies: a retrospective comparison with marrow transplantation. Blood 1996; 88: 2794–2800.
Russel JA, Brown C, Bowen T, Luider J, Ruether JD, Stewart D et al. Allogeneic blood cell transplants for haematological malignancy: preliminary comparison between outcomes with BM transplantation. Bone Marrow Transplant 1996; 18: 703–708.
Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA et al. Immune reconstitution after allogeneic bone marrow transplantation compared with blood stem cell transplantation. Blood 2001; 97: 3380–3389.
Shenoy S, Mohanakumar T, Todd G, Westhoff W, Dunnigan K, Adkins DR et al. Immune reconstitution following allogeneic peripheral blood stem cell transplants. Bone Marrow Transplant 1999; 23: 335–346.
Storek J, Joseph A, Espino G, Dawson MA, Douek DC, Sullivan KM et al. Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation. Blood 2001; 98: 3505–3512.
Schulenburg A, Fischer M, Kalhs P, Mitterbauer M, Rabitsch W, Greinix HT et al. Immune recovery after conventional and non-myeloablative allogeneic stem cell transplantation. Leuk Lymphoma 2005; 46: 1755–1760.
Abrahamsen IW, Somme S, Heldal D, Egeland T, Kvale D, Tjonnfjord GE . Immune reconstitution after allogeneic stem cell transplantation: the impact of stem cell source and graft-versus-host-disease. Haematologica 2005; 90: 86–93.
Hakki M, Riddel SR, Storek J, Carter RA, Stevens-Ayers T, Sudour P et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy and subclinical reactivation. Blood 2003; 102: 3060–3067.
Barrett J, Childs R . Non-myeloablative stem cell transplants. Br J Haematol 2000; 11: 6–17.
Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G 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 non-malignant hematologic diseases. Blood 1998; 91: 756–763.
Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C 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.
Behringer D, Bertz H, Schmoor C, Berger C, Dwenger A, Finke J . Quantitative lymphocyte subset reconstitution after allogeneic hematopoietic transplantation from matched related donors with CD34+ selected PBPC grafts, unselected PBPC grafts or BM grafts. Bone Marrow Transplant 1999; 24: 295–302.
Calvelli T, Denny TN, Paxton H, Gelman R, Kagan J . Guideline for flow cytometric immunophenotyping: a report from the National Institute of Allergy and Immunologic diseases, Division of AIDS. Cytometry 1993; 14: 702–715.
Ottinger HD, Beelen DW, Scheulen B, Schaefer UW, Grosse-Wilde H . Improved immune reconstitution after allotransplantation of peripheral blood stem cells instead of bone marrow. Blood 1996; 88: 2775–2779.
Korbling M, Huh YO, Durett A, Mirza N, Miller P, Engel H et al. Allogeneic blood stem cell transplantation: peripheralisation and yield of donor-derived primitive hematopoietic progenitor cells (CD34+ Thy-1 dim) and lymphocyte subsets, and possible predictors of engraftment and graft-versus-host disease. Blood 1995; 86: 2842–2848.
Michie CA, McLean A, Alcock C, Beverley PC . Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 1992; 360: 264–265.
Small TN, Papadopoulos EB, Boulad F, Black P, Castro-Malaspina H, Childs BH et al. Comparison of immune reconstitution after unrelated and related T cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. Blood 1999; 93: 467–480.
Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G 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 non-malignant hematologic diseases. Blood 1998; 91: 756–763.
Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C 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.
Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S 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.
Saito T, Kanda Y, Nakai K, Kim SW, Arima F, Kami M et al. Immune reconstitution following reduced-intensity transplantation with cladribine, busulfan, and antithymocyte globulin: serial comparison with conventional myeloablative transplantation. Bone Marrow Transplant 2003; 32: 601–608.
Jimenez M, Martinez C, Ercilla G, Carreras E, Urbano-Ispiuza A, Aymerich M et al. Reduced-intensity conditioning regimen preserves thymic function in the early period after hematopoietic stem cell transplantation. Exp Hematol 2005; 33: 1240–1248.
Maris M, Boeckh M, Storer B, Dawson M, White K, Keng M et al. Immunologic recovery after hematopoietic cell transplantation with nonmyeloablative conditioning. Exp Hematol 2003; 31: 941–952.
Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE . Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 1996; 156: 4609–4616.
Mackall CL, Granger L, Sheard MA, Cepeda R, Gress RE . T cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny. Blood 1993; 82: 2585–2594.
Dolstra H, Van de Wiel-van Kemenade E, De Witte T, Preijers F . Clonal predominance of cytomegalovirus-specific CD8+ cytotoxic T lymphocytes in bone marrow recipients. Bone Marrow Transplant 1996; 18: 339–345.
Mackus WJ, Frakking FN, Grummels A, Gamadia LE, de Bree GJ, Hamann D et al. Expansion of CMV-specific CD8+CD45RA+CD27− T cells in B-cell chronic lymphocytic leukemia. Blood 2003; 102: 1057–1063.
Li CR, Greenberg PD, Gilbert MJ, Goodrich JM, Riddell SR . Recovery of HLA-restricted cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. Blood 1994; 83: 1971–1979.
Gregori S, Bacchetta R, Hauben E, Battaglia M, Roncarolo MG . Regulatory T cells: prospective for clinical application in hematopoietic stem cell transplantation. Curr Opin Hematol 2005; 12: 451–456.
Zorn E . CD4+25+ regulatory T cells in human hematopoietic cell transplantation. Semin Cancer Biol 2006; 16: 150–159.
Storek J, Witherspoon RP, Webb D, Storb R . Lack of B cell precursors in marrow transplant recipients with chronic graft-versus-host disease. Am J Hematol 1996; 52: 82–89.
Storek J, Wells D, Dawson MA, Storer B, Maloney DG . Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood 2001; 98: 489–491.
Abrahamsen IW, Somme S, Heldal D, Egeland T, Kvale D, Tjonnfjord GE . Immune reconstitution after allogeneic stem cell transplantation: the impact of stem cell source and graft-versus-host disease. Haematologica 2005; 90: 86–93.
Seddik M, Seemayer TA, Lapp WS . T cell functional defect associated with thymid epithelial cell injury induced by a graft-versus-host reaction. Transplantation 1980; 29: 61–66.
Bahceci E, Epperson D, Douek DC, Melenhorst JJ, Childs RC, Barret AJ . Early reconstitution of the T-cell repertoire after non-myeloablative peripheral blood stem cell transplantation is from post-thymic T-cell expansion and is unaffected by graft-versus-host disease or mixed chimaerism. Br J Haematol 2003; 122: 934–943.
Keever CA, Small TN, Flomenberg N, Heller G, Pekle K, Black P et al. Immune reconstitution following bone marrow transplantation: comparison of recipients of T-cell depleted marrow with recipients of conventional marrow grafts. Blood 1989; 73: 1340–1350.
Chan EY, Chiu EK, So MK, Lie AK, Chan TK . Peripheral blood lymphocyte subsets after allogeneic bone marrow transplantation: reconstitution and correlation with the occurrence of acute graft-versus-host disease. Asian Pac J Allergy Immunol 1994; 12: 117–123.
Acknowledgements
We thank Rita Fröhlich, Uschi Habig-Buchwald, Marion Riedl and Catrin Stroehlein for expert technical assistance, Elisabeth Lenartz for transplant coordination, Irmgard Matt for data management and Professor Roland Mertelsmann for his continuous support.
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Heining, C., Spyridonidis, A., Bernhardt, E. et al. Lymphocyte reconstitution following allogeneic hematopoietic stem cell transplantation: a retrospective study including 148 patients. Bone Marrow Transplant 39, 613–622 (2007). https://doi.org/10.1038/sj.bmt.1705648
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DOI: https://doi.org/10.1038/sj.bmt.1705648
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