Rôle de l’activation des cellules « Natural Killer » par le « missing self » dans la génération de lésions de rejet vasculaire chronique après transplantation d’organe

Abstract : Organ transplantation is the best treatment for terminal organ failure. However, long-term outcome of organ transplantation remains limited by inexorable loss of graft function, which the prevalent dogma links to the microvascular inflammation (MVI) triggered by the recipient's antibody response against alloantigens (antibody-mediated chronic rejection, AMR). Analysing a cohort of 129 renal transplant patients with MVI on graft biopsy, we found that, in half of the cases, histological lesions were not mediated by antibodies. In these patients, genetic studies revealed a higher prevalence of mismatches between donor HLA-I and inhibitory Killer-cell immunoglobulin-receptors (KIR) of recipient's NK cells. We hypothesized that the allogeneic nature of graft endothelium could create a "pseudo-missing self" situation, thereby the recipient's NK cells exposed to inflammatory stimuli would not receive HLA I-mediated inhibitory signals from donor endothelial cells. In co-culture experiments with human NK cells and endothelial cells, we demonstrated that the lack of self HLA-I on endothelial cells can activate NK. This activation triggers mTOR pathway in NK, which can be blocked by rapamycin, a commercially available inhibitor of mTORC1. Finally, we confirmed the existence of missing self-induced rejection and its sensitivity to mTOR inhibition in a murine heart transplantation model. Our work identifies a new type of chronic rejection, exclusively mediated by innate NK cells, with the same detrimental impact on graft survival as AMR. However, while no therapy is available for AMR, mTOR inhibitors efficiently prevent the development of lesions in murine models of NK cell-mediated chronic vascular rejection
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Alice Koenig. Rôle de l’activation des cellules « Natural Killer » par le « missing self » dans la génération de lésions de rejet vasculaire chronique après transplantation d’organe. Immunologie. Université de Lyon, 2018. Français. ⟨NNT : 2018LYSE1158⟩. ⟨tel-02176029⟩

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