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.
Highlights
Solid allograft transplantation can be lifesaving at the point of organ failure
Induced regulatory T cell (TREG) cells are critically dependent on transforming growth factor – beta (TGF-β) for the induction of their key transcription factor, FoxP3.4 The vital role of TREGS in transplant tolerance is apparent where deletion of TREGS in mice already tolerant of kidney allografts leads to allograft rejection.[5]
We found a significant increase in the proportion of CD4+CD25+ TREGS (Figure 3D) and decrease in TEFF/MEM populations in ERT2Cre+Mir142fl/fl mice when compared with control mice at day 8 in secondary lymphoid tissue sites (Figure 3D,E)
Summary
Solid allograft transplantation can be lifesaving at the point of organ failure. long-term allograft and patient survival depends on sustained drug-induced immunosuppression. Induction of tolerance is a major goal in transplantation, potentially allowing withdrawal of immunosuppression and indefinite allograft survival.[2] Regulatory T cells (TREG) are a subset of CD4+ T cells that exert dominant suppression of TEFF responses.[3] Peripherally induced TREG cells are critically dependent on transforming growth factor – beta (TGF-β) for the induction of their key transcription factor, FoxP3.4 The vital role of TREGS in transplant tolerance is apparent where deletion of TREGS in mice already tolerant of kidney allografts leads to allograft rejection.[5] In human studies, the expression of FoxP3 in transplant infiltrating T cells is associated with donor-specific hyporesponsiveness and improved graft histological findings.[6]. MiR-142 over-expression is highly predictive of acute T cell–mediated rejection in renal allograft biopsies and is increased in peripheral blood mononuclear cells (PBMC) of patients with chronic antibody-mediated rejection.[14,15] miR-142 has been shown to be up-regulated in B lymphocyte subsets of PBMCs in operationally tolerant renal transplant patients.[16,17] Whether miR-142 plays a functional role in transplant rejection and what that role may be, has not previously been explored
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