Role of transplantation-related factors in the recovery of the lymphocyte compartment following allogeneic hematopoietic stem cell transplantation
DOI:
https://doi.org/10.14748/e7gmet41Keywords:
immune reconstitution, allogeneic stem cell transplantation, lymphocytesAbstract
Introduction:
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. Post-transplant immune reconstitution is influenced by various factors including donor type, conditioning regimen, graft-versus-host disease (GVHD), and infections. Due to the heterogeneity in immune recovery, monitoring lymphocyte dynamics is essential.
Aim:
The aim of this study was to assess the dynamics of immune reconstitution following allo-HSCT and to evaluate the impact of diagnosis, donor characteristics, and conditioning regimens on lymphocyte subset recovery.
Materials and Methods:
We retrospectively analyzed 89 allo-HSCT recipients. Immune reconstitution was assessed by the quantification of absolute lymphocyte counts and specific lymphocyte subsets (CD3⁺CD4⁺, CD8⁺CD38⁺, CD3⁺CD16/56⁺ NK cells, and CD19⁺ B cells) by flow cytometry analysis on days +30, +100, +180, and +270 post-transplant. Standard statistical methods were used, and p-values were considered significant at p < 0.05.
Results:
Immune recovery varied by diagnosis, with acute myeloid leukemia (AML) patients showing higher CD8⁺CD38⁺ and CD19⁺ cell levels than those with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). Donor type significantly affected lymphocyte recovery: related donors led to higher CD3⁺CD4⁺ and CD19⁺ counts compared to unrelated or haploidentical donors. Male donor grafts were associated with higher absolute lymphocyte count (ALC) and CD3⁺CD4⁺ levels. Conditioning regimens also influenced recovery; FluBuATG resulted in lower CD3⁺CD4⁺ counts compared to BuCyATG and TBF-ATG.
Conclusion:
Immune reconstitution after allo-HSCT is shaped by multiple transplant-related factors. Robust recovery was observed in AML patients and those receiving grafts from related male donors. FluBuATG conditioning was linked to delayed CD4⁺ T-cell recovery. These findings support personalized monitoring to improve post-transplant outcomes.
References
[1] Stem Cell Trialists' Collaborative Group. 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 Aug 1;23(22):5074-87. doi: 10.1200/JCO.2005.09.020. DOI: https://doi.org/10.1200/JCO.2005.09.020
[2] Arnaout K, Patel N, Jain M, et al. Complications of Allogeneic Hematopoietic Stem Cell Transplantation. Cancer Invest. 2014 Aug 9;32(7):349–62. doi: 10.3109/07357907.2014.919301. DOI: https://doi.org/10.3109/07357907.2014.919301
[3] Antin JH. Immune reconstitution: The major barrier to successful stem cell transplantation. Biol Blood Marrow Transplant. 2005 Feb;11(2 Suppl 2):43-5. doi: 10.1016/j.bbmt.2004.11.010. DOI: https://doi.org/10.1016/j.bbmt.2004.11.010
[4] Naik S, Vasileiou S, Aguayo-Hiraldo P, et al. Toward Functional Immune Monitoring in Allogeneic Stem Cell Transplant Recipients. Biol Blood Marrow Transplant. 2020 May;26(5):911–9. doi: 10.1016/j.bbmt.2020.01.005. DOI: https://doi.org/10.1016/j.bbmt.2020.01.005
[5] Storek J, Geddes M, Khan F, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol. 2008 Dec 24;30(4):425–37. doi: 10.1007/s00281-008-0132-5. DOI: https://doi.org/10.1007/s00281-008-0132-5
[6] Toubert A, Glauzy S, Douay C, et al. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again. Tissue Antigens. 2012 Feb 6;79(2):83–9. doi: 10.1111/j.1399-0039.2011.01820.x. DOI: https://doi.org/10.1111/j.1399-0039.2011.01820.x
[7] Storek J, Zhao Z, Lin E, et al. Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases). Clinical Immunology. 2004 Dec;113(3):285–98. doi: 10.1016/j.clim.2004.07.006. DOI: https://doi.org/10.1016/j.clim.2004.07.006
[8] Hurley C, Wade J, Oudshoorn M, et al. Histocompatibility testing guidelines for hematopoietic stem cell transplantation using volunteer donors: report from The World Marrow Donor Association. Bone Marrow Transplant. 1999 Jul 1;24(2):119–21. doi: 10.1038/sj.bmt.1701879. DOI: https://doi.org/10.1038/sj.bmt.1701879
[9] Zino E. A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation. Blood. 2003 Oct 23;103(4):1417–24. doi: 10.1182/blood-2003-04-1279. DOI: https://doi.org/10.1182/blood-2003-04-1279
[10] Wu L, Li CL, Shortman K. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J Exp Med. 1996 Sep 1;184(3):903–11. doi: 10.1084/jem.184.3.903. DOI: https://doi.org/10.1084/jem.184.3.903
[11] Kim HT, Armand P, Frederick D, et al. Absolute Lymphocyte Count Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome. Biol Blood Marrow Transplant. 2015 May;21(5):873–80. doi: 10.1016/j.bbmt.2015.01.019. DOI: https://doi.org/10.1016/j.bbmt.2015.01.019
[12] Loren AW, Bunin GR, Boudreau C, et al. Impact of Donor and Recipient Sex and Parity on Outcomes of HLA-Identical Sibling Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2006 Jul;12(7):758–69. doi: 10.1016/j.bbmt.2006.03.015. DOI: https://doi.org/10.1016/j.bbmt.2006.03.015
[13] Simpson E, Scott D, Chandler P. The Male-Specific Histocompatibility Antigen, H-Y:A History of Transplantation, Immune Response Genes, Sex Determination and Expression Cloning. Annu Rev Immunol. 1997 Apr;15(1):39–61. doi: 10.1146/annurev.immunol.15.1.39. DOI: https://doi.org/10.1146/annurev.immunol.15.1.39
[14] Popli R, Sahaf B, Nakasone H, et al. Clinical impact of H-Y alloimmunity. Immunol Res. 2014 May 30;58(2–3):249–58. doi: 10.1007/s12026-014-8514-3. DOI: https://doi.org/10.1007/s12026-014-8514-3
[15] Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy. Immunol Rev. 1997 Jun 9;157(1):125–40. doi: 10.1111/j.1600-065x.1997.tb00978.x. DOI: https://doi.org/10.1111/j.1600-065X.1997.tb00978.x
[16] Brickner AG. Mechanisms of Minor Histocompatibility Antigen Immunogenicity: The Role of Infinitesimal Versus Structurally Profound Polymorphisms. Immunol Res. 2006;36(1–3):33–42. doi: 10.1385/IR:36:1:33. DOI: https://doi.org/10.1385/IR:36:1:33
[17] Rebibou JM, Chabod J, Dupont I, et al. The interest of flow cytometry for the detection of pregnancy-induced alloimmunization. Transplant Proc. 2000 Dec;32(8):2747. doi: 10.1016/s0041-1345(00)01864-9. DOI: https://doi.org/10.1016/S0041-1345(00)01864-9
[18] Verdijk RM, Kloosterman A, Pool J, et al. Pregnancy induces minor histocompatibility antigen–specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy. Blood. 2004 Mar 1;103(5):1961–4. doi: 10.1182/blood-2003-05-1625. DOI: https://doi.org/10.1182/blood-2003-05-1625
[19] Spierings E. Minor histocompatibility antigens: past, present, and future. Tissue Antigens. 2014 Oct 29;84(4):374–360. doi: 10.1111/tan.12445. DOI: https://doi.org/10.1111/tan.12445
[20] Servais S, Lengline E, Porcher R, et al. Long-Term Immune Reconstitution and Infection Burden after Mismatched Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2014 Apr;20(4):507–17. doi: 10.1016/j.bbmt.2014.01.001 DOI: https://doi.org/10.1016/j.bbmt.2014.01.001
[21] Wils EJ, van der Holt B, Broers AEC, et al. Insufficient recovery of thymopoiesis predicts for opportunistic infections in allogeneic hematopoietic stem cell transplant recipients. Haematologica. 2011 Dec 1;96(12):1846–54. doi: 10.3324/haematol.2011.047696. DOI: https://doi.org/10.3324/haematol.2011.047696
[22] McCune JS, Mager DE, Bemer MJ, et al. Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. Cancer Chemother Pharmacol. 2015 Jul 17;76(1):85–96. doi: 10.1007/s00280-015-2768-x. DOI: https://doi.org/10.1007/s00280-015-2768-x
[23] Nakai K, Mineishi S, Kami M, 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 Jun;75(12):2135–44. doi: 10.1097/01.TP.0000066453.32263.F7. DOI: https://doi.org/10.1097/01.TP.0000066453.32263.F7
[24] Small TN, Avigan D, Dupont B, et al. Immune reconstitution following T-cell depleted bone marrow transplantation: effect of age and posttransplant graft rejection prophylaxis. Biol Blood Marrow Transplant. 1997 Jun;3(2):65–75.
[25] Bosch M, Dhadda M, Hoegh-Petersen M, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy. 2012 Sep;14(10):1258–75. doi: 10.3109/14653249.2012.715243. DOI: https://doi.org/10.3109/14653249.2012.715243