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 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (23)
Sarah Hamada
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Jack Beadle
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London
Alice Koenig
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Basile Sugranes
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
John Ferdinand
Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology
Chien-Chia Chen
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Virginie Mathias
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Maeva Eloudzeri
Pathology Laboratory, Hôpital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris
Thomas Barba
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Helena Paidassi
Carole Saison
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Valérie Dubois
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Emmanuel Morelon
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon
Thierry Walzer
Antoine Marçais
Maud Rabeyrin
Pathology Laboratory, Hospices Civils de Lyon, Groupement Hospitalier Est
Marion Rabant
Pathology Laboratory, Hôpital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris
Patrick Bruneval
Maud Racapé
Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration
Jean Paul Duong Van Huyen
Pathology Laboratory, Hôpital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris
Menna R. Clatworthy
Candice Roufosse
Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London
Olivier Thaunat
Centre International de Recherche en Immunologie, Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon