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Transplantation tolerance in nonhuman primates and humans

Bone Marrow Transplantation volume 54, pages 815–821 (2019)Cite this article

Abstract

This review focuses on our recent studies involving nonmyeloablative bone marrow transplantation as an approach to inducing organ allograft tolerance across MHC barriers in nonhuman primates and in patients. The clinical studies are focused on mechanisms of tolerance involved in a protocol carried out at Massachusetts General Hospital in HLA-mismatched haploidentical combinations for the induction of renal allograft tolerance. These studies, in which chimerism was only transient and GVHD did not occur, suggest an early role for donor-specific regulatory T cells in tolerance induction, followed by partial and gradual deletion of donor-reactive T cells. We utilized high-throughput sequencing methodologies in a novel way to identify and track large numbers of alloreactive T cell receptors (TCRs). This method has been shown to identify biologically significant alloreactive TCRs in transplant patients and pointed to clonal deletion as a major mechanism of long-term tolerance in these patients. More recently, we adapted this sequencing method to optimally identify the donor-specific regulatory T cell (Treg) repertoire. Interrogation of the early posttransplant repertoire demonstrated expansion of donor-specific Tregs in association with tolerance. Our studies suggest a role for the kidney graft in tolerance by these mechanisms in patients who had only transient chimerism. Nonhuman primate studies indicate that other organs, including the heart, the lungs and the liver, are less readily tolerated following a period of transient mixed chimerism. Our efforts to extend the reach of mixed chimerism for tolerance induction beyond the kidney are therefore focused on the addition of recipient Tregs to the protocol. This approach has the potential to enhance chimerism while further reducing the risk of GVHD.

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Acknowledgements

The authors thank Nicole Casio for assistance with the manuscript.

Funding

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award UM1 AI109565. The study was also supported by NIAID grants RO1 AI084074 and PO1 AI106697, the ITN grant NO1 AI015416, and by PO1 CA111519. NHP studies were supported by NIH grants RO1 OD017949 and R56 AI122332. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic.

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Authors and Affiliations

  1. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA

    Megan Sykes & Adam D. Griesemer

  2. Department of Medicine, Columbia University Medical Center, New York, NY, USA

    Megan Sykes

  3. Department of Microbiology & Immunology, Columbia University Medical Center, New York, NY, USA

    Megan Sykes

  4. Department of Surgery, Columbia University Medical Center, New York, NY, USA

    Megan Sykes & Adam D. Griesemer

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Correspondence to Megan Sykes.

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MS is chairman of the scientific advisory board of ITB-MED AB. MS serves as Scientific Advisory Board member and owns equity in Magenta Therapeutics, and received grant support from United Therapeutics, Lung Biotechnology, ITB-Med AB. Additional co-author has declared that no conflict of interest exists.

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Sykes, M., Griesemer, A.D. Transplantation tolerance in nonhuman primates and humans. Bone Marrow Transplant 54 (Suppl 2), 815–821 (2019). https://doi.org/10.1038/s41409-019-0620-3

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