Sarah Hamada, Jack Beadle, Alice Koenig, Basile Sugranes, John R. Ferdinand, Chien‐Chia Chen, Virginie Mathias, Maëva Eloudzeri, Thomas Barba, Helena Paidassi, Carole Saison, V. Dubois, E. Morelon, Thierry Walzer, Antoine Marçais, Maud Rabeyrin, Marion Rabant, Patrick Bruneval, Maud Racapé, Jean Paul Duong Van Huyen, Menna R. Clatworthy, Candice Roufosse, O. Thaunat
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.
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.