[en] The risk of cytomegalovirus (CMV) infection is higher after HLA-matched unrelated donor (URD) than after HLA-matched related donor (MRD) nonmyeloablative hematopoietic cell transplantation (HCT). We therefore investigated factors affecting immune recovery in 94 patients given HCT from MRDs (n = 51) and URDs (n = 43) after 2-Gy total body irradiation with or without fludarabine and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. CD4 T cells counts remained below normal values during the first year after HCT in both patient groups. This included abnormally low counts each of naive CD4 T cells and memory CD4 T cells. Conversely, CD8 T cell counts reached the 10th percentile of normal 6 months after HCT in MRD and URD recipients. On day 30 after HCT, URD recipients had lower counts of B cells (P = .02), naive CD4 T cells (P = .04), memory CD4 T cells (P = .005), memory CD8 T cells (P = .005), and CMV-specific T helper cells (P = .007) than had MRD recipients. This delay in CMV-specific immune reconstitution translated into increased frequency of CMV antigenemia among URD recipients during the first 100 days after HCT. Older donor age was associated with low counts of naive CD4 T cells on days 180-365 after HCT (P = .003). Further, low numbers of T cells and CD34(+) cells in the graft and development of acute graft-versus-host disease were associated with impaired immune recovery of naive CD4 T cells and B cells. In summary, immunologic recovery was poor the first year after nonmyeloablative conditioning and was delayed among URD recipients in comparison with MRD recipients. Other factors significantly associated with delayed immune recovery were advanced donor age, low numbers of CD34 and T cells in the graft, and development of graft-versus-host disease. (C) 2006 American Society for Blood and Marrow Transplantation.
Disciplines :
Surgery Immunology & infectious disease Hematology
Author, co-author :
Baron, Frédéric ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie
Storer, Barry; Fred Hutchinson Cancer Research Center > Clinical Research Division / University of Washington > School of Medicine
Maris, Michael B.; University of Calgary - U of C.
Storek, Jan; Fred Hutchinson Cancer Research Center > Clinical Research Division
Piette, Fanny; Fred Hutchinson Cancer Research Center > Clinical Research Division
Metcalf, Monja; Fred Hutchinson Cancer Research Center > Clinical Research Division
White, Kristen; Fred Hutchinson Cancer Research Center > Clinical Research Division
Sandmaier, Brenda M.; Fred Hutchinson Cancer Research Center > Clinical Research Division / University of Washington > School of Medicine
Maloney, David G.; Fred Hutchinson Cancer Research Center > Clinical Research Division / University of Washington > School of Medicine
Storb, Rainer; Fred Hutchinson Cancer Research Center > Clinical Research Division / University of Washington > School of Medicine
Boeckh, Michael; Fred Hutchinson Cancer Research Center > Clinical Research Division / University of Washington > School of Medicine
Language :
English
Title :
Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning
Publication date :
November 2006
Journal title :
Biology of Blood and Marrow Transplantation
ISSN :
1083-8791
eISSN :
1523-6536
Publisher :
Elsevier Science Inc, New York, United States - New York
Baron F., Maris M.B., Sandmaier B.M., et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 23 (2005) 1993-2003
Maris M.B., Sandmaier B.M., Storer B.E., et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant 12 (2006) 454-465
Morecki S., Gelfand Y., Nagler A., et al. Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloablative regimen. Bone Marrow Transplant 28 (2001) 243-249
Baron F., Schaaf-Lafontaine N., Humblet-Baron S., et al. T-cell reconstitution after unmanipulated, CD8-depleted or CD34-selected nonmyeloablative peripheral blood stem-cell transplantation. Transplantation 76 (2003) 1705-1713
D'Sa S., Peggs K., Pizzey A., et al. T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions. Br J Haematol 123 (2003) 309-322
Maris M., Boeckh M., Storer B., et al. Immunologic recovery after hematopoietic cell transplantation with nonmyeloablative conditioning. Exp Hematol 31 (2003) 941-952
Bahceci E., Epperson D., Douek D.C., Melenhorst J.J., Childs R.C., and Barrett A.J. 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 122 (2003) 934-943
Mohty M., Mohty A.M., Blaise D., et al. Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen. Bone Marrow Transplant 33 (2004) 839-846
Dodero A., Carrabba M., Milani R., et al. Reduced-intensity conditioning containing low-dose alemtuzumab before allogeneic peripheral blood stem cell transplantation: graft-versus-host disease is decreased but T-cell reconstitution is delayed. Exp Hematol 33 (2005) 920-927
Lamba R., Carrum G., Myers G.D., et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with alemtuzumab. Bone Marrow Transplant 36 (2005) 797-802
Baron F., Baker J.E., Storb R., et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 104 (2004) 2254-2262
Hakim F.T., Memon S.A., Cepeda R., et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115 (2005) 930-939
Naylor K., Li G., Vallejo A.N., et al. The influence of age on T cell generation and TCR diversity. J Immunol 174 (2005) 7446-7452
Hirayama M., Azuma E., Jiang Q., et al. The reconstitution of CD45RBhiCD4+ naive T cells is inversely correlated with donor age in murine allogeneic haematopoietic stem cell transplantation. Br J Haematol 111 (2000) 700-707
Junghanss C., Storb R., Maris M.B., et al. Impact of unrelated donor status on the incidence and outcome of cytomegalovirus infections after non-myeloablative allogeneic stem cell transplantation. Br J Haematol 123 (2003) 662-670
McSweeney P.A., Niederwieser D., Shizuru J.A., et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97 (2001) 3390-3400
Maris M.B., Niederwieser D., Sandmaier B.M., et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102 (2003) 2021-2030
Junghanss C., Marr K.A., Carter R.A., et al. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 8 (2002) 512-520
Storek J., Dawson M.A., Storer B., et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 97 (2001) 3380-3389
Li T.S., Tubiana R., Katlama C., Calvez V., Ait M.H., and Autran B. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351 (1998) 1682-1686
Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol 126 (1981) 1614-1619
Clouse K.A., Adams P.W., and Orosz C.G. Enumeration of viral antigen-reactive helper T lymphocytes in human peripheral blood by limiting dilution for analysis of viral antigen-reactive T-cell pools in virus-seropositive and virus-seronegative individuals. J Clin Microbiol 27 (1989) 2316-2323
Baron F., Maris M.B., Storer B.E., et al. High doses of transplanted CD34+ cells are associated with rapid T-cell engraftment and lessened risk of graft rejection, but not more graft-versus-host disease after nonmyeloablative conditioning and unrelated hematopoietic cell transplantation. Leukemia 19 (2005) 822-828
Baron F., Maris M.B., Storer B.E., et al. HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with chronic myeloid leukemia. Biol Blood Marrow Transplant 11 (2005) 272-279
Parkman R., and Weinberg K.I. Immunological reconstitution following hematopoietic stem cell transplantation. In: Thomas E.D., Blume K.G., and Forman S.J. (Eds). Hematopoietic Cell Transplantation. 2nd ed (1999), Blackwell Science, Boston 704-711
Storek J., and Witherspoon R.P. Immunological reconstitution after hemopoietic stem cell transplantation. In: Atkinson K., Champlin R., Ritz J., Fibbe W.E., Ljungman P., and Brenner M.K. (Eds). Clinical Bone Marrow and Blood Stem Cell Transplantation (2004), Cambridge University Press, Cambridge 194-226
Crooks G.M., Weinberg K., and Mackall C. Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 12 (2006) 42-46
Eyrich M., Wollny G., Tzaribaschev N., et al. Onset of thymic recovery and plateau of thymic output are differentially regulated after stem cell transplantation in children. Biol Blood Marrow Transplant 11 (2005) 194-205
Hochberg E.P., Chillemi A.C., Wu C.J., et al. Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 98 (2001) 1116-1121
Storek J., Dawson M.A., and Maloney D.G. Correlation between the numbers of naive T cells infused with blood stem cell allografts and the counts of naive T cells after transplantation. Biol Blood Marrow Transplant 9 (2003) 781-784
Lewin S.R., Heller G., Zhang L., et al. Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood 100 (2002) 2235-2242
Sportes C., McCarthy N.J., Hakim F., et al. Establishing a platform for immunotherapy: clinical outcome and study of immune reconstitution after high-dose chemotherapy with progenitor cell support in breast cancer patients. Biol Blood Marrow Transplant 11 (2005) 472-483
Storek J., Joseph A., Dawson M.A., Douek D.C., Storer B., and Maloney D.G. Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation. Transplantation 73 (2002) 1154-1158
Reusser P., Riddell S.R., Meyers J.D., and Greenberg P.D. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78 (1991) 1373-1380
Li C.-R., Greenberg P.D., Gilbert M.J., Goodrich J.M., and Riddell S.R. 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 83 (1994) 1971-1979
Boeckh M., Leisenring W., Riddell S.R., et al. Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101 (2003) 407-414
Nakamura R., Battiwalla M., Solomon S., et al. Persisting posttransplantation cytomegalovirus antigenemia correlates with poor lymphocyte proliferation to cytomegalovirus antigen and predicts for increased late relapse and treatment failure. Biol Blood Marrow Transplant 10 (2004) 49-57
Hakki M., Riddell S.R., Storek J., et al. Immune reconstitution to cytomegalovirus after allogeneic hematopoietic stem cell transplantation: impact of host factors, drug therapy, and subclinical reactivation. Blood 102 (2003) 3060-3067
Noel D.R., Witherspoon R.P., Storb R., et al. Does graft-versus-host disease influence the tempo of immunologic recovery after allogeneic human marrow transplantation?. An observation on 56 long-term survivors. Blood 51 (1978) 1087-1105
Dulude G., Roy D.C., and Perreault C. The effect of graft-versus-host disease on T cell production and homeostasis. J Exp Med 189 (1999) 1329-1342
Storek J., Wells D., Dawson M.A., Storer B., and Maloney D.G. Factors influencing B-lymphopoiesis after allogeneic hematopoietic cell transplantation. (brief report). Blood 98 (2001) 489-491
Poulin J.F., Sylvestre M., Champagne P., et al. Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease. Blood 102 (2003) 4600-4607
Talvensaari K., Clave E., Douay C., et al. A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation. Blood 99 (2002) 1458-1464
Sharp A., Kukulansky T., and Globerson A. In vitro analysis of age-related changes in the developmental potential of bone marrow thymocyte progenitors. Eur J Immunol 20 (1990) 2541-2546
Kimmig S., Przybylski G.K., Schmidt C.A., et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med 195 (2002) 789-794
Linton P.J., and Dorshkind K. Age-related changes in lymphocyte development and function. (review). Nat Immunol 5 (2004) 133-139