Premium
Dominant regulation of long‐term allograft survival is mediated by microRNA‐142
Author(s) -
Anandagoda Nelomi,
Roberts Luke B.,
Willis Joanna C. D.,
Sarathchandra Padmini,
Xiao Fang,
Jackson Ian,
Hertweck Arnulf,
Kapoor Puja,
Jenner Richard G.,
Howard Jane K.,
Lord Graham M.
Publication year - 2020
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15907
Subject(s) - immunosuppression , medicine , major histocompatibility complex , context (archaeology) , immunology , transplantation , allotransplantation , immune tolerance , immune system , biology , paleontology
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 (T REG ). This leads to increased T REG sensitivity to transforming growth factor – beta and promotes transplant tolerance via an augmented peripheral T REG 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.