Age‐related immune cell dynamics influence outcomes after allogeneic haematopoietic cell transplantation

An efficient immunological reconstitution construes the pillar for the success of allogeneic haematopoietic cell transplantation (HCT) in haematological disorders. Factors influencing post-transplant immune recovery have been largely investigated across multiple cohorts issuing heterogeneous results. Differences in outcomes in adult and paediatric populations suggest an age-related contribution to post-transplant immune reconstitution; however, it is unclear how recipient and donor age may affect the dynamics of single immune cells. Here, we retrospectively collected and analysed immunological data of 174 patients (58 children and 116 adults) consecutively transplanted for haematological disorders in our centre. We show that trajectories of specific immune cells were strictly dependent on recipient age and pretransplant virus exposure, with the strongest effect seen on T CD4+ and B-cell counterparts, while donor age and transplant platforms had a minimal impact. This mirrored different kinetics of immune reconstitution in adult and paediatric patients, with major divergences in immune cell composition in late post-transplant phases, featuring better survival, relapse-free survival and cumulative incidence of pathogen-specific infections in younger patients. Altogether, these findings underpin the importance of recipient age on post-transplant immune cell recovery and define the basic dynamics of the immune reconstitution in paediatric and adult populations as a benchmark for future studies.

[1]  V. Visconte,et al.  Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond , 2022, Frontiers in Immunology.

[2]  S. Mancuso,et al.  Effects of B-Cell Lymphoma on the Immune System and Immune Recovery after Treatment: The Paradigm of Targeted Therapy , 2022, International journal of molecular sciences.

[3]  A. Schulz,et al.  Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions , 2022, Frontiers in Pediatrics.

[4]  Christopher A. Miller,et al.  Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes , 2021, Proceedings of the National Academy of Sciences.

[5]  M. Perales,et al.  Antithymocyte globulin exposure in CD34+ T-cell–depleted allogeneic hematopoietic cell transplantation , 2021, Blood advances.

[6]  P. Chevallier,et al.  Improved outcome in children compared to adolescents and young adults after allogeneic hematopoietic stem cell transplant for acute myeloid leukemia: a retrospective study from the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) , 2021, Journal of Cancer Research and Clinical Oncology.

[7]  N. Kröger,et al.  One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors , 2021, Haematologica.

[8]  J. Pidala,et al.  Increased infections and delayed CD4+ T-cell but faster B-cell Immune Reconstitution after Posttransplant Cyclophosphamide Compared to Conventional GVHD prophylaxis in Allogeneic Transplantation. , 2021, Transplantation and cellular therapy.

[9]  T. LaFramboise,et al.  Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation , 2021, JCI insight.

[10]  G. Kroemer,et al.  Hallmarks of T cell aging , 2021, Nature Immunology.

[11]  N. Bejanyan,et al.  Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation , 2021, Life.

[12]  Catherine J. Wu,et al.  Impaired T- and NK-cell reconstitution after haploidentical HCT with posttransplant cyclophosphamide. , 2021, Blood advances.

[13]  M. V. D. van den Brink,et al.  An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation , 2021, Frontiers in Oncology.

[14]  J. Gommerman,et al.  B cell depletion therapies in autoimmune disease: advances and mechanistic insights , 2020, Nature Reviews Drug Discovery.

[15]  A. Huitema,et al.  CD4+ T-cell reconstitution predicts Survival Outcomes after acute Graft-versus-Host-Disease; a dual center validation. , 2020, Blood.

[16]  M. Gönen,et al.  Genetic and environmental determinants of human TCR repertoire diversity , 2020, Immunity & Ageing.

[17]  Marc Ansari,et al.  Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation , 2019, Leukemia.

[18]  M. Robin,et al.  EBV-associated post-transplant lymphoproliferative disease in patients who received anti-CD 20 after hematopoietic stem cell transplantation. , 2019, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[19]  G. Tonon,et al.  Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation , 2019, Nature Medicine.

[20]  S. Montoto,et al.  The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies , 2019, Bone Marrow Transplantation.

[21]  J. Ritz,et al.  Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial. , 2018, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[22]  Christopher A. Miller,et al.  Immune Escape of Relapsed AML Cells after Allogeneic Transplantation , 2018, The New England journal of medicine.

[23]  A. Gratwohl,et al.  Hematopoietic stem cell transplantation activity in Europe , 2013, Current opinion in hematology.

[24]  D. Maloney,et al.  Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. , 2012, Cytotherapy.

[25]  Y. Shyr,et al.  Long-term impact of prior rituximab therapy and early lymphocyte recovery on auto-SCT outcome for diffuse large B-cell lymphoma , 2012, Bone Marrow Transplantation.

[26]  J. Ritz,et al.  Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. , 2011, Blood.

[27]  H. Einsele,et al.  Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. , 2010, Blood.

[28]  Heather E. Lynch,et al.  Thymic involution and immune reconstitution. , 2009, Trends in immunology.

[29]  J. Passweg,et al.  Reconstitution of the immune system after hematopoietic stem cell transplantation in humans , 2008, Seminars in Immunopathology.

[30]  Human subject protection; foreign clinical studies not conducted under an investigational new drug application. Final rule. , 2008, Federal register.

[31]  A. Fischer,et al.  Haematopoietic stem cell transplantation trends in children over the last three decades: a survey by the paediatric diseases working party of the European Group for Blood and Marrow Transplantation , 2007, Bone Marrow Transplantation.

[32]  C. Siegrist,et al.  Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. , 2000, Blood.

[33]  R. Collins,et al.  Assessment of thymic output in adults after haematopoietic stemcell transplantation and prediction of T-cell reconstitution , 2000, The Lancet.