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

Nelomi Anandagoda, Luke Roberts, Joanna C.D. Willis, Padmini Sarathchandra, Fang Xiao, Ian Jackson, Arnulf Hertweck, Puja Kapoor, Richard G. Jenner, Jane Howard, Graham M. Lord

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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 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.

Original languageEnglish
Article numberdoi.org/10.1111/ajt.15907
Pages (from-to)2715-2727
Number of pages13
JournalAmerican Journal of Transplantation
Volume20
Issue number10
Early online date10 Apr 2020
DOIs
Publication statusPublished - 1 Oct 2020

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

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