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).