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Les signaux de danger dans l'initiation de la réponse immunitaire contre le facteur VIII thérapeutique

Abstract : Hemophilia A (HA) is a rare congenital hemorrhagic disorder resulting from a defective production of coagulation factor VIII (FVIII). Treatment of HA patients with therapeutic FVIII results, in up to 30% of the cases, in the emergence of anti-FVIII antibodies that inhibit the pro-coagulant activity of the therapeutically administered FVIII. FVIII endocytosis by dendritic cells (DCs) and its presentation to T cells have been well established. However, the nature of the danger signals responsible for the maturation of DCs that is mandatory to the initiation of anti-FVIII immune response, remains poorly understood. During my thesis, I investigated the origin of these danger signals, and explored 3 possibilities: an origin linked to the intrinsic structure of FVIII, to the inflammatory environment that prevails before FVIII administration, or to the inflammatory environment generated upon injection of exogenous FVIII. My work demonstrates that FVIII is not able to trigger macrophages maturation or to induce direct TLR2 activation. I also rejected the hypothesis of a role of a compensatory activation state of HA patients' platelets (PLT) in the initiation of the immune response against FVIII in a murine model of HA. My results suggest that PLT involvement depends on their activation by thrombin which is generated by FVIII administration. The identification of the inflammatory mediators released by activated PLT should open attractive therapeutic perspectives in the control of inflammation at the time of FVIII administration, in order to reduce FVIII immunogenicity.
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  • HAL Id : tel-00839224, version 1

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Maud Teyssandier. Les signaux de danger dans l'initiation de la réponse immunitaire contre le facteur VIII thérapeutique. Immunologie. Université Pierre et Marie Curie - Paris VI, 2012. Français. ⟨NNT : 2012PAO66476⟩. ⟨tel-00839224⟩

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