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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,17]]},"abstract":"<jats:p>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 impact, combining CNI with mTOR inhibitors (mTORinh) synergistically reduced NK cell activation and endothelial damage. In a pilot clinical study involving 50 renal transplant recipients with MS-associated NK cell\u2013mediated microvascular inflammation, patients who tolerated mTORinh introduced on top of CNI at diagnosis demonstrated reduced MVI lesions and improved graft survival compared to a historical cohort left on CNI and mycophenolate mofetil. This translational study identifies mTOR inhibition as a pivotal adjunct to CNI in mitigating MS-associated NK cell\u2013mediated inflammation, potentially improving long-term graft outcomes.<\/jats:p>","DOI":"10.1073\/pnas.2516594123","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T17:47:32Z","timestamp":1770832052000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Dual inhibition of mTOR and calcineurin pathways mitigates missing self\u2013induced NK cell\u2013mediated microvascular rejection"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6676-4705","authenticated-orcid":false,"given":"Sarah","family":"Hamada","sequence":"first","affiliation":[{"name":"Centre International de Recherche en Immunologie, Universit\u00e9 de Lyon, INSERM U1111, Universit\u00e9 Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Sup\u00e9rieure de 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