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Spatiotemporal in vivo tracking of polyclonal human regulatory T cells (Tregs) reveals a role for innate immune cells in Treg transplant recruitment

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)324-336
Number of pages13
JournalMolecular Therapy - Methods and Clinical Development
Volume20
Early online date9 Dec 2020
DOIs
E-pub ahead of print9 Dec 2020
Published12 Mar 2021

Bibliographical note

Funding Information: We thank Drs. D. Boardman, J. Bordoloi, and E. Skourti for technical assistance and F. Laniyan for help with animal husbandry and logistics. This work was supported by the British Heart Foundation (RG/13/12/30395), the MRC Centre for Transplantation at King's College London (MR/J006742/1), Cancer Research UK (C48390/A21153), and the Wellcome/EPSRC Centre for Medical Engineering (WT203148/Z/16/Z). This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas? NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Conceptualization, F.M.M-B. G.L. G.O.F. L.A.S. and R.I.L.; Data Curation, J.J. S.N. G.O.F. and G.L.; Formal Analysis, A.V. J.J. Q.P. S.L.T. S.N. and Y.R.M.; Funding Acquisition, G.L. and G.O.F.; Investigation, A.V. C.S. J.J. L.A.S. Q.P. R.F.H. S.L.T. S.N. and Y.R.M.; Methodology, A.V. C.S. L.A.S. and S.N.; Project Administration, L.A.S. G.O.F. and G.L.; Resources, L.A.S. R.F.H. and Q.P.; Supervision, G.L. G.O.F. and L.A.S.; Validation, J.J. Q.P. S.L.T. and S.N.; Visualization, G.O.F. and J.J.; Writing ? Original Draft, G.L. and G.O.F.; Writing ? Review & Editing, all authors. G.L. is a co-founder of Quell Therapeutics. S.L.T. and Y.R.M. are employed by Quell Therapeutics (all data contributed by S.L.T. and Y.R.M. were collected before being employed by Quell Therapeutics). Funding Information: We thank Drs. D. Boardman, J. Bordoloi, and E. Skourti for technical assistance and F. Laniyan for help with animal husbandry and logistics. This work was supported by the British Heart Foundation ( RG/13/12/30395 ), the MRC Centre for Transplantation at King's College London ( MR/J006742/1 ), Cancer Research UK ( C48390/A21153 ), and the Wellcome/EPSRC Centre for Medical Engineering ( WT203148/Z/16/Z ). This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London and/or the NIHR Clinical Research Facility . The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Regulatory T cells (Tregs) are emerging as a new cell-based therapy in solid organ transplantation. Adoptive transfer of Tregs has been shown preclinically to protect from graft rejection, and the safety of Treg therapy has been demonstrated in clinical trials. Despite these successes, the in vivo distribution and persistence of adoptively transferred Tregs remained elusive, which hampers clinical translation. Here we isolated human Tregs using a GMP-compatible protocol and lentivirally transduced them with the human sodium iodide symporter to render them traceable in vivo by radionuclide imaging. Engineered human Tregs were characterized for phenotype, survival, suppressive capacity, and reporter function. To study their trafficking behavior, they were subsequently administered to humanized mice with human skin transplants. Traceable Tregs were quantified in skin grafts by non-invasive nano-single-photon emission computed tomography (nanoSPECT)/computed tomography (CT) for up to 40 days, and the results were validated ex vivo. Using this approach, we demonstrated that Treg trafficking to skin grafts was regulated by the presence of recipient Gr-1+ innate immune cells. We demonstrated the utility of radionuclide reporter gene-afforded quantitative Treg in vivo tracking, addressing a fundamental need in Treg therapy development and offering a clinically compatible methodology for future Treg therapy imaging in humans.

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