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Probing the function of dermal macrophages by lectin targeting for potential application to autoimmune diseases (DERMACRO)
Date du début: 1 juin 2013, Date de fin: 31 mai 2017 PROJET  TERMINÉ 

"Autoimmune diseases originate from a breakdown in tolerance leading to immune responses against self antigens and chronic inflammation. The main effector cells are self-specific T cells and B cells, the latter producing auto-antibodies. This results in progressive destruction of organs. Because patients must rely on long anti-inflammatory treatment, autoimmune diseases take a significant toll on European public health systems.An optimal treatment would consist in a specific control of anti-self immune responses, without compromising the ability to fight infections and cancer. Antigen-presenting cells (APCs) that control the fate of self-specific T cells represent an attractive target, because abnormal differentiation of T cells is a critical turning point in most autoimmune diseases. Moreover, T cells are responsible for immune memory, and establish throughout the whole body. Therefore, APC-targeting therapy could be administered briefly and provide sustained, systemic benefits over long periods of time, similarly to a vaccine.In skin-involving autoimmunity, deleterious effector cells accumulate in the dermis. As opposed to dendritic cells (DCs), dermal macrophages (dMphs) keep skin immune responses in check. Although dMphs would be easily accessible to drugs, no effort has been undertaken to exploit their tolerogenic potential.Mphs and DCs take up glycosylated proteins via endocytic receptors called lectins. Anti-lectin antibodies have been used to convey antigens to DCs and control immunity. A novel approach consists in using the exceptional affinity of arbovirus envelope proteins (E-proteins) for lectins specific of dMphs.We will evaluate the capacity of E-proteins for antigen delivery and stimulation of the tolerogenic potential of dMphs in 3 steps: (1) Create targeting reagents by chemical coupling to E-proteins (2) Analyse the effects of E-protein-conjugates on dMphs (3) Determine the influence of targeted dMphs on T cell responses in vitro and in vivo."