Development of original therapeutic molecules to treat lupus and TNBC patients.
ABSTRACT: Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disease associated with a degradation of different organs (kidneys, skin, joints, brain, lung, heart). In collaboration with teams from Bordeaux and Nottingham Universities, Legembre group (Centre Eugène Marquis, Inserm ERL440 – OSS, University Rennes-1) demonstrated that in SLE patients, CD95L (also known as FasL) is expressed abnormally by the endothelium of blood vessels present in damaged organs of SLE patients. The team showed that after cleavage by metalloprotease, soluble CD95L accelerates the negative evolution of these pathologies.
To do this, the soluble CD95L interacts with its receptor called CD95 (Fas) and induces a calcium signaling pathway promoting the recruitment of the inflammatory T lymphocytes, Th17 cells, in inflamed organs. Accumulation of these Th17 cells contributes to fuel an inflammatory process promoting the degradation of the organs in SLE patients. Also, this Team i) identifies the molecular mechanism by which soluble CD95L recruits Th17 cells (activation of a calcium response) in damaged organs and ii) designs an original therapeutic molecule capable of blocking this signal and thereby reducing clinical symptoms in lupus-prone mice.
In conclusion, this original study highlights a novel therapeutic molecule, which by blocking the migration of Th17 cells prevents the inflammatory process responsible for the aggravation of the pathology in lupus patients. Moreover, the same group is evaluating if this therapeutic compound can also prevent tumor relapse in triple negative breast cancer patients.
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