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The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment

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Abstract

As the thymus represents the primary site of T-cell development, optimal thymic function is of paramount importance for the successful reconstitution of the adaptive immunity after allogeneic hematopoietic stem cell transplantation. Thymus involutes as part of the aging process and several factors, including previous chemotherapy treatments, conditioning regimen used in preparation to the allograft, occurrence of graft-versus-host disease, and steroid therapy that impair the integrity of the thymus, thus affecting its role in supporting T-cell neogenesis. Although the pathways governing its regeneration are still poorly understood, the thymus has a remarkable capacity to recover its function after damage. Measurement of both recent thymic emigrants and T-cell receptor excision circles is valuable tools to assess thymic output and gain insights on its function. In this review, we will extensively discuss available data on factors regulating thymic function after allogeneic hematopoietic stem cell transplantation, as well as the strategies and therapeutic approaches under investigation to promote thymic reconstitution and accelerate immune recovery in transplanted patients, including the use of cytokines, sex-steroid ablation, precursor T-cells, and thymus bioengineering. Although none of them is routinely used in the clinic, these approaches have the potential to enhance thymic function and immune recovery, not only in patients given an allograft but also in other conditions characterized by immune deficiencies related to a defective function of the thymus.

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Funding

E.V. was supported by grants from the Amy Strelzer Manasevit Research Program; the Italian Association for Cancer Research (AIRC); and the Italian Ministry of Health (“Ricerca Corrente”). F.L. was supported by grants from AIRC (Special Program Metastatic disease: the key unmet need in oncology 5 per mille 2018 Project Code 21147 and Accelerator Award 2017 INCAR); Ministero dell’Istruzione, dell’Università e della Ricerca, PRIN ID 2017 WC8499_004; Ministero della Salute, RF-2016-02364388. A.T. and E.C. were supported by the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence “Milieu Intérieur” Grant ANR-10-LABX-69-01 and by the by the Agence Nationale de la Recherche (Project RANKLthym ANR-19- CE18-0021-02).

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Author notes

  1. Enrico Velardi, Emmanuel Clave, Franco Locatelli and Antoine Toubert contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Bambino Gesù Children’s Hospital, IRCCS, 00146, Rome, Italy

    Enrico Velardi & Franco Locatelli

  2. Université de Paris, Institut de Recherche Saint Louis, EMiLy, Inserm U1160, F-75010, Paris, France

    Emmanuel Clave & Antoine Toubert

  3. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden

    Lucas C. M. Arruda

  4. Department of Maternal and Child Health, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy

    Francesca Benini & Franco Locatelli

  5. Laboratoire d’Immunologie et d’Histocompatibilité, AP-HP, Hopital Saint-Louis, F-75010, Paris, France

    Antoine Toubert

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  1. Enrico Velardi
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  4. Francesca Benini
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Corresponding author

Correspondence to Enrico Velardi.

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Conflict of interest

E.V. has acted as a consultant and received honorarium from Ferring Pharmaceuticals. Two provisional patent applications have been filed (US 15/033,178 and US 62/566,897) with E.V. listed as inventor. F.L. participated in advisory boards or speakers bureaus for Amgen, Novartis, Bellicum Pharmaceutical, Miltenyi, Medac, Neovii, Jazz Pharmaceutical and Takeda. A.T., F.B., and E.C. have no conflict of interest.

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This article is a contribution to the special issue on: The thymus and autoimmunity - Guest Editor: Georg Holländer.

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Velardi, E., Clave, E., Arruda, L.C.M. et al. The role of the thymus in allogeneic bone marrow transplantation and the recovery of the peripheral T-cell compartment. Semin Immunopathol 43, 101–117 (2021). https://doi.org/10.1007/s00281-020-00828-7

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