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Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients

Bone Marrow Transplantation volume 50, pages S77–S81 (2015)Cite this article

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Abstract

Age-related decline in thymic function is a well-described process that results in reduced T-cell development and thymic output of new naïve T cells. Thymic involution leads to reduced response to vaccines and new pathogens in otherwise healthy individuals; however, reduced thymic function is particularly detrimental in clinical scenarios where the immune system is profoundly depleted such as after chemotherapy, radiotherapy, infection and shock. Poor thymic function and restoration of immune competence has been correlated with an increased risk of opportunistic infections, tumor relapse and autoimmunity. Apart from their primary role in sex dimorphism, sex steroid levels profoundly affect the immune system in general and, in fact, age-related thymic involution has been at least partially attributed to the increase in sex steroids at puberty. Subsequently it has been demonstrated that the removal of sex steroids, or sex steroid ablation (SSA), triggers physiologic changes that ultimately lead to thymic re-growth and improved T-cell reconstitution in settings of hematopoietic stem cell transplant (HSCT). Although the cellular and molecular process underlying these regenerative effects are still poorly understood, SSA clearly represents an attractive therapeutic approach to enhance thymic function and restore immune competence in immunodeficient individuals.

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Acknowledgements

This research was supported by the National Institutes of Health award nos R01-HL069929 (MRMvdB), R01-AI080455 (MRMvdB), R01-AI101406 (MRMvdB), P01-CA023766 (RJO) and Project 4 of P01-CA023766 (MRMvdB). Support was also received from the US National Institute of Allergy and Infectious Diseases (NIAID Contract HHSN272200900059C), the Experimental Therapeutics Center of MSKCC funded by Mr. William H. Goodwin and Mrs. Alice Goodwin, the Lymphoma Foundation, Alex's Lemonade Stand, the Geoffrey Beene Cancer Research Center at MSKCC and the Susan and Peter Solomon Divisional Genomics Program. This project has received funding from the European Union’s Seventh Programme for Research, Technological Development and demonstration under grant agreement no (602587). EV was supported by fellowships from the Italian Foundation for Cancer Research and the Italian Society of Pharmacology and a New Investigator Award from the American Society for Blood and Marrow Transplantation. JAD was supported by a CJ Martin fellowship from the Australian National Health and Medical Research Council; a Scholar Award from the American Society of Hematology; and a K99 career transition award from the National Institutes of Health (1K99CA176376).

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Authors and Affiliations

  1. Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    E Velardi, J A Dudakov & M R M van den Brink

  2. Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy

    E Velardi

  3. Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Melbourne, Victoria, Australia

    J A Dudakov

  4. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    M R M van den Brink

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Correspondence to M R M van den Brink.

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Competing interests

Professor MRMvdB has received consulting or advisory fees from Merck & Co, Yobira Therapeutics, Boehringer Ingelheim, and has received lecture fees from Merck & Co, Novartis Pharma A.G., Novartis Institute for Biomedical Research, Tobira Therapeutics, Boehringer Ingelheim and Regeneron Pharmaceuticals. He has also received grant support from Radiation Effects Research Foundation (RERF), NIH/NHLBI, NIH/NCI, NIH/NIAID and the European Consortium. The remaining authors declare no conflicts of interest.

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This article was published as part of a supplement, supported by WIS-CSP Foundation, in collaboration with Gilead, Milteny Biotec, Gamida cell, Adienne Pharma and Biotech, Medac hematology, Kiadis Pharma, Almog Diagnostic.

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Velardi, E., Dudakov, J. & van den Brink, M. Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients. Bone Marrow Transplant 50 (Suppl 2), S77–S81 (2015). https://doi.org/10.1038/bmt.2015.101

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