[en] BACKGROUND: Background and objective. We investigated immune recovery in 50 patients given either unmanipulated or CD8-depleted allogeneic peripheral blood stem cells after non-myeloablative conditioning. DESIGN AND METHODS: Fifty patients were randomized to receive either CD8-depleted (n=22) or non-manipulated (n=28) peripheral blood stem cells. The median patients age was 57 (range 36-69) years. The conditioning regimen consisted of 2 Gy total body irradiation with or without added fludarabine. Twenty patients received grafts from related donors, 14 from 10/10 HLA-allele matched unrelated donors, and 16 from HLA-mismatched unrelated donors. Graft-versus-host disease pro-phylaxis consisted of mycophenolate mofetil and cyclosporine. Immune recovery during the first year after hematopoietic cell transplantation was assessed by flow cytometry phenotyping, analyses of the diversity of the TCRBV repertoire, and quantification of signal-joint T-cell receptor excision circles (sjTREC). RESULTS: CD8-depletion of the graft reduced the recovery of CD8(+) T-cell counts in the first 6 months following transplantation (p<0.0001) but had no significant impact on the restoration of other T-cell subsets. Both sjTREC concentration and CD3(+) T-cell counts increased significantly between day 100 and 365 (p=0.010 and p=0.0488, respectively) demonstrating neo-production of T cells by the thymus. Factors associated with high sjTREC concentration 1 year after transplantation included an HLA-matched unrelated donor (p=0.029), a high content of T cells in the graft (p=0.002), and the absence of chronic graft-versus-host disease (p<0.0001). CONCLUSIONS: Our data suggest that while immune recovery is mainly driven by peripheral expansion of the graft-contained mature T cells during the first months after non-myeloablative transplantation, T-cell neo-generation by the thymus plays an important role in long term immune reconstitution in transplanted patients.
Research center :
GIGA-I3 - Giga-Infection, Immunity and Inflammation - ULiège
Disciplines :
Hematology
Author, co-author :
Castermans, Emilie ✱; Université de Liège - ULiège > Département des sciences cliniques > Hématologie - Oncologie médicale
Baron, Frédéric ✱; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Willems, Evelyne ; Université de Liège - ULiège > Département des sciences cliniques > Hématologie
Schaaf-Lafontaine, Nicole ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie biologique et immuno hématologie
Meuris, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > Génétique
Gothot, André ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie biologique et immuno hématologie
Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, et al. Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplant comorbidities. Blood 2004;104:961-8.
Baron F, Storb R, Storer BE, Maris MB, Niederwieser D, Shizuru JA, et al. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation. J Clin Oncol 2006;24:4150-7.
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005;23:1993-2003.
Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplants (HCT) from HLA-matched related (MRD) and unrelated (URD) donors for patients with hematologic malignancies using low-dose TBI conditioning. Blood 106 (Part 1)[11], 194a, #655. 11-16-2005.
Maris MB, Sandmaier BM, Storer BE, Maloney DG, Shizuru JA, Agura E, et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of post-grafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant 2006;12:454-65.
Morecki S, Gelfand Y, Nagler A, Or R, Naparstek E, Varadi G, et al. Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloablative regimen. Bone Marrow Transplant 2001;28:243-9.
Baron F, Schaaf-Lafontaine N, Humblet-Baron S, Meuris N, Castermans E, Baudoux E, et al. T-cell reconstitution after unmanipulated, CD8-depleted or CD34-selected nonmyeloablative peripheral blood stem-cell transplantation. Transplantation 2003;76:1705-13.
D'Sa S, Peggs K, Pizzey A, Verfuerth S, Thuraisundaram D, Watts M, 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 2003;123:309-22.
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;31:941-52.
Bahceci E, Epperson D, Douek DC, Melenhorst JJ, Childs RC, Barrett 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;122:934-43.
Mohty M, Mohty AM, Blaise D, Faucher C, Bilger K, Isnardon D, et al. Cytomegalovirus-specific immune recovery following allogeneic HLA-identical sibling transplantation with reduced-intensity preparative regimen. Bone Marrow Transplant 2004;33:839-46.
Dodero A, Carrabba M, Milani R, Rizzo E, Raganato A, Montefusco V, 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 2005;33:920-7.
Lamba R, Carrum G, Myers GD, Bollard CM, Krance RA, Heslop HE, et al. Cytomegalovirus (CMV) infections and CMV-specific cellular immune reconstitution following reduced intensity conditioning allogeneic stem cell transplantation with alemtuzumab. Bone Marrow Transplant 2005;36:797-802.
Baron F, Storer B, Maris MB, Storek J, Piette F, Metcalf M, et al. Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning. Biol Blood Marrow Transplant 2006;12:1176-87.
Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, et al. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol 2007;25:690-7.
Chao NJ, Liu CX, Rooney B, Chen BJ, Long GD, Vredenburgh JJ, et al. Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells. Biol Blood Marrow Transplant 2002;8:249-56.
Storek J, Witherspoon RP. Immunological reconstitution after hemopoietic stem cell transplantation. In: Atkinson K, Champlin R, Ritz J, Fibbe WE, Ljungman P, Brenner MK, editors. Clinical Bone Marrow and Blood Stem Cell Transplantation. Cambridge, UK: Cambridge University Press, 2004:194-226.
Crooks GM, Weinberg K, Mackall C. Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 2006;12 [1 Suppl 1]:42-6.
Peggs KS. Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans. Cytotherapy 2006;8:427-36.
Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 2000;355:1875-81.
Storek J, Dawson MA, Maloney DG. 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 2003;9:781-4.
Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, et al. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 2001;97:1458-66.
Hochberg EP, Chillemi AC, Wu CJ, Neuberg D, Canning C, Hartman K, et al. Quantitation of T-cell neogenesis in vivo after allogeneic bone marrow transplantation in adults. Blood 2001; 98:1116-21.
Lewin SR, Heller G, Zhang L, Rodrigues E, Skulsky E, van den Brink MR, et al. Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood 2002;100: 2235-42.
Jiménez M, Martínez C, Ercilla G, Carreras E, Urbano-Ispízua A, Aymerich M, et al. Clinical factors influencing T-cell receptor excision circle (TRECs) counts following allogeneic stem cell transplantation in adults. Transpl Immunol 2006;16:52-9.
Poulin JF, Sylvestre M, Champagne P, Dion ML, Kettaf N, Dumont A, 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 2003;102: 4600-7.
Baron F, Baker JE, Storb R, Gooley TA, Sandmaier BM, Maris MB, et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2004;104:2254-62.
Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. The influence of age on T cell generation and TCR diversity. J Immunol 2005; 174:7446-52.
Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005;115:930-9.
Nimer SD, Giorgi J, Gajewski JL, Ku N, Schiller GJ, Lee K, et al. Selective depletion of CD8+ cells for prevention of graft-versus-host disease after bone marrow transplantation. Transplantation 1994;57:82-7.
Giralt S, Hester J, Huh Y, Hirsch-Ginsberg C, Rondón G, Seong D, et al. CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995;86:4337-43.
Alyea EP, Soiffer RJ, Canning C, Neuberg D, Schlossman R, Pickett C, et al. Toxicity and efficacy of defined doses of CD+ donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. Blood 1998; 91:3671-80.
Andersen MK, Larson RA, Mauritzson N, Schnittger S, Jhanwar SC, Pedersen-Bjergaard J. Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop. Genes, Chromosomes Cancer 2002;33: 395-400.
Baron F, Frère P, Baudoux E, Schaaf-Lafontaine N, Fillet G, Beguin Y. 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;88:835-7.
Baron F, Siquet J, Schaaf-Lafontaine N, Baudoux E, Hermanne JP, Fillet G, et al. Pre-emptive immunotherapy with CD8-depleted donor lymphocytes after CD34-selected allogeneic peripheral blood stem cell transplantation. Haematologica 2002; 87:78-88.
Willems E, Castermans E, Baron F et al. Nonmyeloablative stem cell transplantation with CD8-depleted or unmanipulated peripheral blood stem cells: a prospective randomized trial. ASH Annual Meeting Abstracts 2005; 106:1075.
Frère P, Baron F, Bonnet C, Hafraoui K, Pereira M, Willems E, et al. Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen. Bone Marrow Transplant 2006; 37:411-8.
McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;97:3390-400.
Baron F, Maris MB, Storer BE, Sandmaier BM, Panse JP, Chauncey TR, 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 2005; 19:822-8.
Baron F, Sandmaier BM. Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Leukemia 2006;20:1690-700.
Genevée C, Diu A, Nierat J, Caignard A, Dietrich PY, Ferradini L, 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; 22:1261-9.
Dion ML, Poulin JF, Bordi R, Sylvestre M, Corsini R, Kettaf N, et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity 2004;21:757-68.
Dion ML, Bordi R, Zeidan J, Asaad R, Boulassel MR, Routy JP, et al. Slow disease progression and robust therapy-mediated CD4+ T-cell recovery are associated with efficient thymopoiesis during HIV-1 infection. Blood 2007;109:2912-20.
Storek J, Dawson MA, Storer B, Stevens-Ayers T, Maloney DG, Marr KA, et al. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 2001;97:3380-9.
Storek J, Witherspoon RP. Immunologic reconstitution after hematopoietic stem cell transplantation. In: Atkinson K, editor. Clinical Bone Marrow and Blood Stem Cell Transplantation. Cambridge, UK: Cambridge University Press, 2000: 111-46.
Martínez C, Urbano-Ispizua A, Rozman C, Marín P, Rovira M, Sierra J, et al. Immune reconstitution following allogeneic peripheral blood progenitor cell transplantation: Comparison of recipients of positive CD34+ selected grafts with recipients of unmanipulated grafts. Exp Hematol 1999;27:561-8.
Storek J, Joseph A, Dawson MA, Douek DC, Storer B, Maloney DG. Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation. Transplantation 2002; 73:1154-8.
Dulude G, Roy DC, Perreault C. The effect of graft-versus-host disease on T cell production and homeostasis. J Exp Med 1999;189:1329-42.
Hauri-Hohl MM, Keller MP, Gill J, Hafen K, Pachlatko E, Boulay T, et al. Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation. Blood 2007;109:4080-8.
Hakki M, Riddell 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;102:3060-7.
