[en] BACKGROUND: Pre-transplant infusion of rabbit anti-T cell globulin (ATG) is increasingly used as prevention of graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). However, the precise impact of pre-transplant ATG on immune recovery after PBSCT is still poorly documented. METHODS: In the current study, we compared immune recovery after myeloablative PBSCT in 65 patients who either received (n = 37) or did not (n = 28) pre-transplant ATG-Fresenius (ATG-F). Detailed phenotypes of circulating T, B, natural killer (NK) and invariant NKT (iNKT) cells were analyzed by multicolor flow cytometry at serial time-points from day 40 to day 365 after transplantation. Thymic function was also assessed by sjTREC quantification. Serious infectious events were collected up to 2 years post-transplantation. RESULTS: Pre-transplant ATG-F had a prolonged (for at least up to 1-year) and selective negative impact on the T-cell pool, while it did not impair the recovery of B, NK nor iNKT cells. Among T cells, ATG-F selectively compromised the recovery of naive CD4+, central memory CD4+ and naive CD8+ cells, while it spared effector memory T and regulatory T cells. Levels of sjTRECs were similar in both cohorts at 1-year after PBSCT, suggesting that ATG-F unlikely impaired thymopoiesis at long-term after PBSCT. Finally, the incidence and rate of serious infections were similar in both groups, while ATG-F patients had a lower incidence of grade II-IV acute graft-versus-host disease. CONCLUSIONS: Pre-transplant ATG-F induces long-lasting modulation of the circulating T-cell pool after myeloablative PBSCT, that may participate in preventing graft-versus-host disease without deeply compromising anti-pathogen defenses.
Disciplines :
Hematology
Author, co-author :
SERVAIS, Sophie ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Menten-Dedoyart, Catherine
Beguin, Yves ; Université de Liège > GIGA-R : Hématologie
SEIDEL, Laurence ; Centre Hospitalier Universitaire de Liège - CHU > Département de gestion des systèmes d'informations (GSI) > Secteur d'appui à la recherche clinique et biostatistique
Stem Cell Trialists' Collaborative. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005; 23(22): 5074-87. PMID: 16051954
Baron F, Labopin M, Blaise D, Lopez-Corral L, Vigouroux S, Craddock C, et al. Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2014; 49(3): 389-96. doi: 10.1038/bmt.2013.204 PMID: 24419525
Bonifazi F, Solano C, Wolschke C, Patriarca F, Pini M, Nagler A, et al. Prevention of Chronic GvHD after HLA-Identical Sibling Peripheral Hematopietic Stem Cell Transplantation with or without Anti-Lymphocyte Globulin (ATG). Results from a Prospective, Multicenter Randomized Phase III Trial (ATGfamilystudy). ASH abstract Blood. 2014; 124:27.
Devillier R, Furst S, El-Cheikh J, Castagna L, Harbi S, Granata A et al. Antithymocyte globulin in reduced-intensity conditioning regimen allows a high disease-free survival exempt of long-term chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2014; 20(3): 370-4. doi: 10.1016/j.bbmt. 2013.11.030 PMID: 24315846
Finke J, Bethge W, Schmoor C, Ottinger H, Stelljes M, Zander A, et al. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009; 10(9): 855-64. doi: 10.1016/S1470-2045(09)70225-6 PMID: 19695955
Socie G, Schmoor C, BethgeW, Ottinger H, Stelljes M, Zander A, et al. Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius. Blood. 2011; 117(23): 6375-82. doi: 10.1182/blood-2011-01-329821 PMID: 21467544
Soiffer R, Lerademacher J, Ho V, Kan F, Artz A, Champlin R, et al. Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies. Blood. 2011; 117(25): 6963-70. doi: 10.1182/blood-2011-01-332007 PMID: 21464372
Chawla S, Dharmani-Khan P, Liu Y, Prokopishyn N, Amlish Munir M, Griffiths C, et al. High serum level of antithymocyte globulin immediately before graft infusion is associated with a low likelihood of chronic, but not acute, graft-versus-host disease. Biol Blood Marrow Transplant. 2014; 20(8): 1156-62. doi: 10. 1016/j.bbmt.2014.04.007 PMID: 24727330
Remberger M and Sundberg B. Rabbit-immunoglobulin G levels in patients receiving thymoglobulin as part of conditioning before unrelated donor stem cell transplantation. Haematologica. 2005; 90(7): 931-8. PMID: 15996931
Bacigalupo A, Lamparelli T, Bruzzi P, Guidi S, Alessandrino P, di Bartolomeo P, et al. Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO). Blood. 2001; 98(10): 2942-7. PMID: 11698275
Hamadani M, Blum W, Phillips G, Elder P, Andritsos L, Hofmeister C, et al. Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies. Biol Blood Marrow Transplant. 2009; 15(11): 1422-30. doi: 10.1016/j.bbmt.2009.07.006 PMID: 19822302
Wang Y, Fu HX, Liu DH, Xu LP, Zhang XH, Chang YJ, et al. Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transplant. 2014; 49(3): 426-33. doi: 10.1038/bmt.2013.191 PMID: 24292519
Storek J, Mohty M and Boelens JJ. Rabbit Anti-T Cell Globulin in Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2015; 21(6): 959-970. doi: 10.1016/j.bbmt.2014.11.676 PMID: 25482864
Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007; 21(7): 1387-94. PMID: 17410187
Humblet-Baron S. and Baron F., Boosting regulatory T-cell function with the humanized CD4-specific humanized monoclonal antibody Tregalizumab (BT-061). Immunol Cell Biol. 2015; 93(4):321-2 doi: 10. 1038/icb.2014.120 PMID: 25666094
Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy. 2012; 14 (10): 1258-75. doi: 10.3109/14653249.2012.715243 PMID: 22985195
Na I.K., Wittenbecher F, Dziubianau M, Herholz A, Mensen A, Kunkel D, et al. Rabbit antithymocyte globulin (thymoglobulin) impairs the thymic output of both conventional and regulatory CD4+ T cells after allogeneic hematopoietic stem cell transplantation in adult patients. Haematologica. 2013; 98(1): 23-30. doi: 10.3324/haematol.2012.067611 PMID: 22801968
Nakai K, Mineishi S, Kami M, Saito T, Hori A, Kojima R, et al. Antithymocyte globulin affects the occurrence of acute and chronic graft-versus-host disease after a reduced-intensity conditioning regimen by modulating mixed chimerism induction and immune reconstitution. Transplantation. 2003; 75(12): 2135-43. PMID: 12829926
Sairafi D, Mattsson J, Uhlin M, and Uzunel M. Thymic function after allogeneic stem cell transplantation is dependent on graft source and predictive of long term survival. Clin Immunol. 2012; 142(3): 343-50. doi: 10.1016/j.clim.2011.12.001 PMID: 22227522
Mensen A, Na IK, Hafer R, Meerbach A, Schlecht M, Pietschmann ML, et al. Comparison of different rabbit ATG preparation effects on early lymphocyte subset recovery after allogeneic HSCT and its association with EBV-mediated PTLD. J Cancer Res Clin Oncol. 2014; 140(11): 1971-80. doi: 10. 1007/s00432-014-1742-z PMID: 24962343
Roll P, Muhammad K, Stuhler G, Grigoleit U, Einsele H and Tony HP. Effect of ATG-F on B-cell reconstitution after hematopoietic stem cell transplantation. Eur J Haematol. 2015. In press.
Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009; 15(12): 1628-33. doi: 10.1016/j. bbmt.2009.07.004 PMID: 19896087
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15(6): 825-8. PMID: 7581076
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11(12): 945-56. PMID: 16338616
Servais S, Lengline E, Porcher R, Carmagnat M, Peffault de Latour R, Robin M et al. Long-term immune reconstitution and infection burden after mismatched hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014; 20(4): 507-17. doi: 10.1016/j.bbmt.2014.01.001 PMID: 24406505
Ljungman P, Griffiths P and Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002; 34(8): 1094-7. PMID: 11914998
Wingard JR. Opportunistic infections after blood and marrow transplantation. Transpl Infect Dis. 1999; 1(1): 3-20. PMID: 11428967
Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, et al. A scheme for defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow Transplant. 2007; 13 (12): 1469-76. PMID: 18022577
Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R, et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica. 2011; 96(2): 298-306. doi: 10.3324/haematol. 2010.029702 PMID: 20934996
Castermans E, Baron F, Willems E, Schaaf-Lafontaine N, Meuris N, Gothot A, et al. Evidence for neogeneration of T cells by the thymus after non-myeloablative conditioning. Haematologica. 2008; 93(2): 240-7. doi: 10.3324/haematol.11708 PMID: 18223286
Hannon M, Beguin Y, Ehx G, Servais S, Seidel L, Graux C, et al. Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation following Flu-TBI versus TLI-ATG Conditioning. Clin Cancer Res. 2015. In press.
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(13): 4600-7. PMID: 12933579
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME, et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood. 2014; 123(23): 3664-71. doi: 10. 1182/blood-2014-01-552984 PMID: 24744269
Bosch M, Khan FM, and Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol. 2012; 19(4): 324-35. doi: 10.1097/MOH.0b013e328353bc7d PMID: 22517587
Toubert A, Glauzy S, Douay C, and Clave E. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again. Tissue Antigens. 2012; 79 (2): 83-9. doi: 10.1111/j.1399-0039.2011.01820.x PMID: 22220718
Pearl JP, Parris J, Hale DA, Hoffmann SC, Bernstein WB, McCoy KL, et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am J Transplant. 2005; 5(3): 465-74. PMID: 15707400
Krenger W, Blazar BR and Hollander GA. Thymic T-cell development in allogeneic stem cell transplantation. Blood. 2011; 117(25): 6768-76. doi: 10.1182/blood-2011-02-334623 PMID: 21427289
Clave E, Busson M, Douay C, Peffault de Latour R, Berrou J, Rabian C, et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood. 2009; 113(25): 6477-84. doi: 10.1182/blood-2008-09-176594 PMID: 19258596
Anderson BE, McNiff J, Yan J, Doyle H, Mamula M, Shlomchik MJ, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003; 112(1): 101-8. PMID: 12840064
Chen BJ, Cui X, Sempowski GD, Liu C, and Chao NJ. Transfer of allogeneic CD62L-memory T cells without graft-versus-host disease. Blood. 2004; 103(4): 1534-41. PMID: 14551132
Zheng H, Matte-Martone C, Li H, Anderson BE, Venketesan S, Sheng Tan H, et al. Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. Blood. 2008; 111(4): 2476-84. PMID: 18045967
Bleakley M, Heimfeld S, Jones LA, Turtle C, Krause D, Riddell SR, et al. Engineering human peripheral blood stem cell grafts that are depleted of naive T cells and retain functional pathogen-specific memory T cells. Biol Blood Marrow Transplant. 2014; 20(5): 705-16. doi: 10.1016/j.bbmt.2014.01.032 PMID: 24525279
Yakoub-Agha I, Saule P, Depil S, Micol JB, Grutzmacher C, Boulanger-Villard F, et al. A high proportion of donor CD4+ T cells expressing the lymph node-homing chemokine receptor CCR7 increases incidence and severity of acute graft-versus-host disease in patients undergoing allogeneic stem cell transplantation for hematological malignancy. Leukemia. 2006; 20(9): 1557-65. PMID: 16826221
Hannon M, Lechanteur C, Lucas S, Somja J, Seidel L, Belle L, et al. Infusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease. Transfusion. 2014; 54 (2): 353-63. doi: 10.1111/trf.12279 PMID: 23772685
Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013; 5(179): 179ra43. doi: 10.1126/scitranslmed.3005265 PMID: 23552371
