Role of CD95L in Treg function and therapeutics – FasReg

Glomerulonephritis (GN) is a group of immune-mediated diseases and a major cause of end-stage renal disease. Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and lupus nephritis (LN) are autoimmune GN. Glucocorticoids and immunosuppressive drugs are used to control autoimmune GN activity, but their nonspecific mechanism of action and side effects engender a poor safety profile; thereby, these pathologies require the development of tailored therapeutic replacement. The trafficking of Th17 cells in inflamed kidneys contributes to tissue damage. In addition, inflammation is maintained by an impaired function of regulatory T cells (Treg) and a Th17/Treg imbalance. CD95L (also known as FasL) belongs to the tumor necrosis factor (TNF) superfamily. This transmembrane protein (mCD95L) can be cleaved by metalloproteases (MMPs) and a disintegrin and metalloprotease (ADAM) to release a soluble ligand (sCD95L). The receptor of CD95L, CD95 (Fas, APO1) is expressed by all cells in the human body. We observed that sCD95L is upregulated in LN and AAV patients and this factor not only promotes the accumulation of Th17 cells in inflamed kidneys but also inhibits the immunosuppressive activity of Treg cells. This project will attempt to understand how sCD95L prevents the immunosuppressive activity of Treg cells and develop original drugs targeting the process of mCD95L cleavage to finally, evaluate the therapeutic activity of these drugs in AAV and LN-like CD95L humanized mouse models.