Prolongation of allograft survival by passenger donor regulatory T cells.
Harper, Ines G
Claas, Frans HJ
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
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Harper, I. G., Gjorgjimajkoska, O., Siu, J., Parmar, J., Mulder, A., Claas, F. H., Hosgood, S., et al. (2019). Prolongation of allograft survival by passenger donor regulatory T cells.. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 19 (5), 1371-1379. https://doi.org/10.1111/ajt.15212
Tissue resident lymphocytes are present within many organs, and are presumably transferred at transplantation, but their impact upon host immunity is unclear. Here we examine whether transferred donor natural regulatory CD4 T cells (nT-regs) inhibit host alloimmunity and prolong allograft survival. Transfer of donor-strain lymphocytes was first assessed by identifying circulating donor-derived CD4 T cells in 21 consecutive human lung transplant recipients, with three patterns of chimerism apparent: transient; intermediate; and persistent (detectable for up to 6 weeks, 6 months, and beyond one year, respectively). The potential for transfer of donor nT-regs was then confirmed by analysis of leucocyte filters recovered from ex-vivo normothermic perfusion circuits of human kidneys retrieved for transplantation. Finally, in a murine model of cardiac allograft vasculopathy, depletion of donor CD4 nT-regs prior to organ retrieval resulted in markedly accelerated heart allograft rejection and augmented host effector antibody responses. Conversely, adoptive transfer or purified donor-strain nT-regs inhibited host humoral immunity and prolonged allograft survival, and more effectively so than following administration of recipient nT-regs. In summary, following transplantation, passenger donor-strain nT-regs can inhibit host adaptive immune responses and prolong allograft survival. Isolated donor-derived nT-regs may hold potential as a cellular therapy to improve transplant outcomes. This article is protected by copyright. All rights reserved.
Immune System, Animals, Humans, Mice, Isoantibodies, Organ Preservation, Treatment Outcome, Adoptive Transfer, Kidney Transplantation, Heart Transplantation, Lung Transplantation, Transplantation, Homologous, Perfusion, Graft Rejection, Graft Survival, Cell Lineage, Tissue Donors, T-Lymphocytes, Regulatory, Immunity, Humoral, Allografts
This work was supported by a British Heart Foundation project grant, the NIHR Cambridge Biomedical Research Centre and the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation at the University of Cambridge in collaboration with Newcastle University and Royal Papworth Hospital in partnership with NHS Blood and Transplant (NHSBT). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the Department of Health or NHSBT. IGH was supported by a Wellcome Trust Clinical Research Training Fellowships and Raymond and Beverly Sackler Scholarships. IGH received additional support from an Addenbrooke’s Charitable Trust Clinical Research Fellowship. RM was supported by a European Society of Organ Transplantation Junior Basic Science Grant. JHS was supported by a Gates PhD Fellowship.
Wellcome Trust (087808/Z/08/Z)
British Heart Foundation (PG/10/002/28143)
British Heart Foundation (FS/12/87/29899)
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External DOI: https://doi.org/10.1111/ajt.15212
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287558
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/