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Dominant regulation of long-term allograft survival is mediated by microRNA-142

Anandagoda, N; Roberts, L; Willis, JCD; Sarathchandra, P; Xiao, F; Jackson, I; Hertweck, A; ... Lord, GM; + view all (2020) Dominant regulation of long-term allograft survival is mediated by microRNA-142. American Journal of Transplantation , 20 (10) pp. 2715-2727. 10.1111/ajt.15907. Green open access

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Abstract

Organ transplantation is often lifesaving, but the long-term deleterious effects of combinatorial immunosuppression regimens and allograft failure cause significant morbidity and mortality. Long-term graft survival in the absence of continuing immunosuppression, defined as operational tolerance, has never been described in the context of multiple major histocompatibility complex (MHC) mismatches. Here, we show that miR-142 deficiency leads to indefinite allograft survival in a fully MHC mismatched murine cardiac transplant model in the absence of exogenous immunosuppression. We demonstrate that the cause of indefinite allograft survival in the absence of miR-142 maps specifically to the T cell compartment. Of therapeutic relevance, temporal deletion of miR-142 in adult mice prior to transplantation of a fully MHC mismatched skin allograft resulted in prolonged allograft survival. Mechanistically, miR-142 directly targets Tgfbr1 for repression in regulatory T cells (TREG ). This leads to increased TREG sensitivity to TGF-β and promotes transplant tolerance via an augmented peripheral TREG response in the absence of miR-142. These data identify manipulation of miR-142 as a promising approach for the induction of tolerance in human transplantation.

Type: Article
Title: Dominant regulation of long-term allograft survival is mediated by microRNA-142
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/ajt.15907
Publisher version: https://doi.org/10.1111/ajt.15907
Language: English
Additional information: © 2020 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/).
Keywords: animal models: murine, basic (laboratory) research/science, immunobiology, molecular biology, molecular biology: micro RNA, organ transplantation in general, T cell biology, tolerance: experimental, tolerance: mechanisms
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10095622
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