Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants
Journal
Nature communications
Journal Volume
10
Journal Issue
1
Date Issued
2019
Author(s)
Koenig, Alice
Marçais, Antoine
Barba, Thomas
Mathias, Virginie
Sicard, Antoine
Rabeyrin, Maud
Racapé, Maud
Duong-Van-Huyen, Jean-Paul
Bruneval, Patrick
Loupy, Alexandre
Dussurgey, Sébastien
Ducreux, Stéphanie
Meas-Yedid, Vannary
Olivo-Marin, Jean-Christophe
Paidassi, Héléna
Guillemain, Romain
Taupin, Jean-Luc
Callemeyn, Jasper
Morelon, Emmanuel
Nicoletti, Antonino
Charreau, Béatrice
Dubois, Valérie
Naesens, Maarten
Walzer, Thierry
Defrance, Thierry
Thaunat, Olivier
Abstract
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.
Publisher
NATURE PUBLISHING GROUP
Type
journal article