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

TY - JOUR

T1 - Dominant regulation of long‐term allograft survival is mediated by microRNA‐142

AU - Anandagoda, Nelomi

AU - Roberts, Luke

AU - Willis, Joanna C.D.

AU - Sarathchandra, Padmini

AU - Xiao, Fang

AU - Jackson, Ian

AU - Hertweck, Arnulf

AU - Kapoor, Puja

AU - Jenner, Richard G.

AU - Howard, Jane

AU - Lord, Graham M.

N1 - Funding Information: NA is funded by a Wellcome Trust Clinical Research Training Fellowship (107387/Z/15/Z). JCDW is funded by an MRC Clinical Research Training Fellowship (G1002014). This study was supported by grants awarded by the Wellcome Trust to GML and RJ (grant number 091009), the British Heart Foundation to GML (award number PG/12/36/29444) and the MRC to RGJ and GML (grant number MR/M003493/1). GML is also 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. The authors wish to thank Ms Lucy Meader and Dr Anna Nowocin for performing heterotopic heart transplants. 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: © 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 Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - 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 transforming growth factor – beta 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.

AB - 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 transforming growth factor – beta 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.

KW - animal models: murine

KW - basic (laboratory) research/science

KW - immunobiology

KW - molecular biology

KW - molecular biology: micro RNA

KW - organ transplantation in general

KW - T cell biology

KW - tolerance: experimental

KW - tolerance: mechanisms

UR - http://www.scopus.com/inward/record.url?scp=85083799595&partnerID=8YFLogxK

U2 - 10.1111/ajt.15907

DO - 10.1111/ajt.15907

M3 - Article

C2 - 32277570

AN - SCOPUS:85083799595

SN - 1600-6135

VL - 20

SP - 2715

EP - 2727

JO - American Journal of Transplantation

JF - American Journal of Transplantation

IS - 10

M1 - doi.org/10.1111/ajt.15907

ER -