MERIT

Adaptive immunity plays a major role in the pathophysiology of atherosclerosis. Some new drugs, such as Nilotinib, a tyrosine kinase inhibitor used in haematology, induce major cardiovascular side effects with accelerated atherosclerosis. The aim of this research project is to dissect the pathophysiological mechanisms behind the pro-atherogenic effects of Nilotinib. Based on very encouraging data obtained in vitro and in vivo in the Apoe-/- mouse, we hypothesized that Nilotinib alters efferocytosis and promotes the accumulation of apoptotic debris in atherosclerotic plaques via the inhibition of MertK and an IgM B lymphocyte response. Our hypothesis will be evaluated in different mouse models with loss-of-function (Apoe-/-Mertk-/-) or gain-of-function of MertK (Apoe-/-MertkCR). On the other hand, the involvement of the B lymphocyte response will be studied in models with global B2 lymphocyte deficiency (obtained by anti-CD20 depleting antibody) or specific marginal zone B lymphocyte deficiency (Apoe-/-Cd79acre/+Rbpjkflox/flox). The impact of treatments (PBS, Imatinib or Nilotinib) on the development of atherosclerosis and the size of the necrotic core will be quantified after 12 weeks, as will innate and adaptive immune cell functions using various techniques (Histology, immunofluorescence, flow cytometry, qPCR, ELISA). Oxidized LDL antibody levels will be measured in all models. The clinical relevance of our experimental results will be studied on a plasma biobank of patients treated with Nilotinib or Imatinib. This original translational project will shed pathophysiological light on the pro-atherogenic effects of Nilotinib, and could open up prospects for more personalized use of this highly effective haematological drug.