Neuroimmunology and peptide therapy (H. David/S. Muller)
Our group concentrates its research activity on the misdirected immune responses occurring in autoimmune diseases, primarily systemic lupus erythematosus (SLE), and on the discovery of new druggable molecules designed to specifically immunoregulate these diseases.
SLE is a multigenic chronic autoimmune disease characterized by the deposition of autoantibodies and immune complexes, that can affect every organ system and whose etiology still remains largely unknown. Current treatments based on the use of corticosteroids and immunosuppressant have unfortunate side effects, counter-indications and definite toxicity that contribute to disease morbidity.
Some years ago, our group discovered a peptide, which we have called P140, that exhibits impressive protective effects in MRL/lpr mice that develop a strong lupus-like disease. In a multicenter, randomized, placebo-controlled phase-IIb study for lupus, P140/LupuzorTM was found to be safe and met its primary efficacy end points, confirming pre-clinical data generated in MRL/lpr lupus-prone mice. It is currently evaluated in advanced clinical trials of phase III in the US, Europe and Mauritius. P140 peptide was found to bind HSPA8/HSC70 chaperone protein and decrease its expression, which we discovered to be enhanced in lupus conditions. This interaction destabilizes the HSPA8 binding to other chaperones, such as HSP90AA1, and consequently affect its biological activity. We also showed that P140 reduces the autophagic flux in antigen-presenting B cells with an accumulation of macroautophagy markers and a blockade of the excessive chaperone-mediated autophagy process. P140 also decreases the abnormally high MHC molecule expression. These effects contribute all to reduce hyperactivation of T and B cell autoreactivity and production, in fine, of pathogenic autoantibodies.
Our on-going studies are focused on:
-The characterisation, at the cellular and molecular level, of autophagy processes that appear abnormal in several autoimmune and inflammatory conditions and prove to be a decisive hot point in lupus pathology.
-At the pathophysiological level, the alteration - and notably behavioural disturbances - that progressively emerge in model lupus mice and closely mimic the typical clinical signs found in lupus patients.
-The development of peptide-based strategies with the aim of specifically modulating autoreactivity, restoring immune tolerance and reversing the course of diseases in murine models of chronic inflammatory pathologies, especially in neurological and system diseases.
Using a refined battery of reliable tools, we will explore the neurobehavioral impairments occurring in inflammatory diseases and perform behavioural preclinical characterization of novel neuroprotective small molecules, peptides and other bioactive drugs. Cellular and molecular approaches, imaging and immunochemistry will reinforce these behavioural investigations.