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Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants

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Koenig, Alice | Chen, Chien-Chia | Marçais, Antoine | Barba, Thomas | Mathias, Virginie | Sicard, Antoine | Rabeyrin, Maud | Racapé, Maud | Duong-Van-Huyen, Jean-Paul | Bruneval, Patrick | Loupy, Alexandre | Dussurgey, Sebastien | Ducreux, Stéphanie | Meas-Yedid, Vannary | Olivo-Marin, Jean-Christophe | Païdassi, Helena | Guillemain, Romain | Taupin, Jean-Luc | Callemeyn, Jasper | Morelon, Emmanuel | Nicoletti, Antonino | Charreau, Béatrice | Dubois, Valérie | Naesens, Maarten | Walzer, Thierry | Defrance, Thierry | Thaunat, Olivier

Edité par CCSD ; Nature Publishing Group -

International audience. Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

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