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Relationship of post-transplant thymopoiesis with CD4+FoxP3+ regulatory T cell recovery associated with freedom from chronic graft versus host disease

Bone Marrow Transplantation volume 54, pages 917–920 (2019)Cite this article

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Recovery of CD4+FoxP3+ regulatory T cells (Tregs) has been associated with protection from graft versus host disease (GVHD) in adult hematopoietic stem cell transplantation (HSCT), though significant debate exists as to the extent of this influence [1,2,3,4,5,6,7]. The lack of a clearly defined relationship between Tregs and GVHD may be related to heterogeneity of Treg populations, which can differ significantly in their functional responses, proliferative capabilities, tissue homing, and antigenic reactivity [4, 8]. Mechanisms regulating Treg compartment regeneration and function after HSCT are not well-defined, though studies in adult HSCT patients posited that post-transplant Tregs were primarily derived from peripheral expansion of circulating Tregs with minimal contribution from thymopoiesis. The ability of the thymus to reconstitute a functionally self-tolerant T cell compartment is compromised by age-related thymic involution, thymic GVHD, and radiation and chemotherapy. We hypothesized that post-transplant thymopoiesis may be an important factor in restoration of Treg-mediated protection from chronic GVHD (cGVHD), and may be a potential mechanistic explanation for disparate observations of the relationship between Tregs and cGVHD.

As thymus-dependent restoration of T lymphocyte compartments has a larger role in pediatric HSCT owing to lower-thymic function in adults due to age-related thymic involution [9], we examined pediatric HSCT recipients. We examined longitudinal peripheral blood samples and clinical data from 19 pediatric allogeneic HSCT patients (Table S1) collected at 14, 30, 60, 90, 180, 270, and 360 days post transplant. Patients were followed clinically for a mean duration of 16 months post transplant (range 3–24 months), with three patients excluded from analysis due to disease relapse leading to re-transplantation or death within 100 days of HSCT. Patients were divided into two groups, patients that developed cGVHD (n = 7) (Table S2) and patients that remained cGVHD-free for the study duration of at least 12 months (n = 12). Mean time to first diagnosis of cGVHD was 133 days post-transplant (range 101–189 days post-transplant). T cell reconstitution after HSCT was initially assessed by absolute lymphocyte count, and measurement of naive (CD45RA+) and memory (CD45RO+) helper CD4+ and cytotoxic CD8+ T cells by flow cytometry (Fig. S1). These parameters did not differ significantly between patients developing cGVHD and those remaining cGVHD-free.

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Acknowledgements

The authors thank Daniel Douek MD PhD (NIH Vaccine Research Center) for providing TREC control plasmid, clinical trials staff at Rady Children’s Hospital for assistance in patient recruitment, UCSD Moores Cancer Center Biorepository and Tissue Technology Center for sample processing, Jesus Olivera and Cody Fine of the UCSD Human Embryonic Stem Cell Core Facility for flow cytometry cell sorting, and Jack Dixon PhD (UCSD) for use of the CFX96 real-time CR detection system. We thank Ted Ball MD and Jack Bui MD PhD for critical review of the manuscript. This research was supported by National Institutes of Health K08 AI085039, American Society of Hematology Junior Faculty Scholar Award and Bridge Grant, and UCSD Health Sciences Research Grant RQ194R (GPM). This work made possible in part by the California Institute for Regenerative Medicine Major Facilities Grant (FA1-00607) to the Sanford Consortium for Regenerative Medicine.

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  1. These authors contributed equally: Erin M. Trovillion and Nicholas J. Gloude.

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  1. Department of Pediatrics, University of California San Diego, La Jolla, California, USA

    Erin M. Trovillion, Nicholas J. Gloude & Eric J. Anderson

  2. Department of Pathology, University of California San Diego, La Jolla, California, USA

    Gerald P. Morris

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Correspondence to Gerald P. Morris.

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Trovillion, E.M., Gloude, N.J., Anderson, E.J. et al. Relationship of post-transplant thymopoiesis with CD4+FoxP3+ regulatory T cell recovery associated with freedom from chronic graft versus host disease. Bone Marrow Transplant 54, 917–920 (2019). https://doi.org/10.1038/s41409-018-0394-z

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