Dual inhibition of mTOR and calcineurin pathways mitigates missing self-induced NK cell-mediated microvascular rejection.

ABSTRACT: The inability of graft endothelial cells to deliver HLA-I-dependent inhibitory signals to recipient natural killer (NK) cells (missing self, MS), drives donor-specific antibody-independent microvascular inflammation (MVI), leading to graft failure. This study aimed to elucidate the signaling pathways involved in MS-associated NK cell activation and explore therapeutic strategies. Analyses of kidney graft biopsies identified calcium signaling pathways and mTOR as a key regulator of MS-induced NK cell activation. Two experimental models were developed to mimic the pathological condition: in vitro cocultures of human NK cells with allogeneic microvascular endothelial cells and a murine heart transplantation model. These models showed that while calcineurin inhibitor (CNI) alone had a limited

SUBMITTER: Hamada S 

PROVIDER: S-EPMC12912960 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature