Study on NK cells cytotoxicity toward endothelial cells

Abstract : There are several mechanisms by which tumor angiogenesis may be reduced. They are addressed to tumor endothelial cell (EC) to block their activation and proliferation. Among the natural protection mechanisms, natural killer (NK) cells play an important role. Stimulated NK cells may eliminate potentially “dangerous” cells. Hence, we hypothesized that ECs involved in tumor angiogenesis may be recognized as “dangerous” cells and killed by NK cells. First, the adhesive interactions between NK cells and ECs were investigated. Using human in vitro cell lines, molecular mechanisms of NK cells adhesion to ECs under static and flow in vitro conditions were examined, showing that IL-2 activated NK cells were able to adhere to ECs. The molecular mechanism was shown not to be selectin - dependent but integrin and/or C type lectin like - dependent. Subsequently, cytotoxicity of NK cells toward ECs was analyzed. Its molecular mechanism was mainly perforin-granzyme dependent. NK cells were shown to induce in target ECs Bid translocation and cytochrome c releasing. To validate in vitro cellular model most of these experiments were repeated with freshly isolated human blood NK cells. The in vivo approach necessitated that adhesion and cytotoxicity were performed using murine ECs lines and freshly isolated NK cells from murine spleen. It was found that IL-12 synergizes with IL-2 to stimulate NK cells killing activity toward ECs. The demonstration that, under specific conditions stimulated NK cells are able to kill ECs in vitro allows hypothesizing that in vivo NK cells may participate in tumor angiogenesis inhibition.
Keywords : Angiogenesis
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Theses
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Aleksandra Bielawska. Study on NK cells cytotoxicity toward endothelial cells. Agricultural sciences. Université d'Orléans, 2009. English. ⟨NNT : 2009ORLE2008⟩. ⟨tel-00452681⟩

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