Dual inhibition of mTOR and calcineurin pathways mitigates missing self–induced NK cell–mediated microvascular rejection
- Sarah Hamada
- Jack Beadle
- Alice Koenig
- Basile Sugranes
- John Ferdinand
- Chien-Chia Chen
- Virginie Mathias
- Maeva Eloudzeri
- Thomas Barba
- Helena Paidassi
- Carole Saison
- Valérie Dubois
- Emmanuel Morelon
- Thierry Walzer
- Antoine Marcais
- Maud Rabeyrin
- Marion Rabant
- Patrick Bruneval
- Maud Racapé
- Jean Paul Duong Van Huyen
- Menna R. Clatworthy
- Candice Roufosse
- Olivier Thaunat
2026-02-11
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–mediated 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–mediated inflammation, potentially improving long-term graft outcomes.