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

Publication by CIRI on November 25, 2019.

Dogma in transplantation holds that microvascular inflammation (MVI) triggered by recipient’s antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Analysis of a cohort of 129 renal recipients with MVI on graft biopsy shows that, in half of the cases, histological lesions are not mediated by antibodies. In these patients, genetic studies reveal a higher prevalence of mismatches between donor HLA I and recipient inhibitory KIR receptors. Human in vitro models and transplantation of ’2-microglobulin-/- hearts into WT mice demonstrate that the allogeneic nature of graft endothelium creates a "pseudomissing self" situation, thereby the recipient’s NK cells exposed to inflammatory stimuli do not receive HLA I-mediated inhibitory signals from donor endothelial cells. Missing self-induced activation of NK cells depends on mTORC1 and rapamycin, a commercially available mTOR inhibitor, efficiently prevents the development of this new type of chronic vascular rejection in a preclinical model.

Source: . Alice Koenig, Chien-Chia Chen, Antoine Marçais, Thomas Barba, Virginie Mathias, Antoine Sicard, Maud Rabeyrin, Maud Racapé, Jean-Paul Duong-Van-Huyen, Patrick Bruneval, Alexandre Loupy, Sébastien Dussurgey, Stéphanie Ducreux, Vannary Meas-Yedid, Jean-Christophe Olivo-Marin, Héléna Paidassi, Romain Guillemain, Jean-Luc Taupin, Jasper Callemeyn, Emmanuel Morelon, Antonino Nicoletti, Béatrice Charreau, Valérie Dubois, Maarten Naesens, Thierry Walzer, Thierry Defrance & Olivier Thaunat. Nature Communications volume 10, Article number: 5350 (2019).

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