PhD defence: Alice KOENIG
Date / Heure
Date(s) - 21/09/2018
14 h 00 min - 17 h 00 min
Amphi Pasteur, Tour CERVI
PhD defence: Alice KOENIG, team «Effector and memory B lymphocytes», september 21th 2018 at 14h00 in Amphi Pasteur, tour CERVI.
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.
Composition du jury:
Pr. Blancho Gilles, PU-PH, Université de Nantes, Nantes, Président
Dr. Mooney Nuala, Directrice de recherche, CNRS, Paris, Rapporteure
Dr. You Sylvaine, Chargée de Recherche, INSERM, Paris, Rapporteure
Pr. Belot Alexandre, PU-PH, Université Claude Bernard Lyon 1, Lyon, Examinateur
Dr. Charreau Béatrice, Biochimiste, Université de Nantes, Nantes, Examinatrice
Dr. Marçais Antoine, Chargé de Recherche, INSERM, Lyon, Examinateur
Pr. Thaunat Olivier, PU-PH, Université Claude Bernard Lyon 1, Lyon, Directeur de thèse