No abstract

Human endogenous retroviruses (HERVs), known to represent 8% of the human genome, have been associated with several autoimmune diseases. In particular, the envelope protein of HERV-W family (HERV-W-Env), which has been involved in the pathogenesis of Multiple Sclerosis (MS), displays pro-inflammatory and autoimmune properties. This has initially been demonstrated in an MS context, but it subsequently turned out to be relevant for type 1 diabetes (T1D). We recently observed that HERV-W-Env protein and RNA are detected respectively in sera and PBMC of more than 50% of T1D patients. We demonstrated that this pathogenic protein is expressed by acinar cells in human T1D pancreas, and is associated with the recruitment of macrophages within the pancreas of these patients. HERV-W-Env also displays direct pathogenic properties, as it inhibits insulin secretion by human Langerhans islets. In this new report, we present data from two transgenic mouse models in which HERV-W-Env is expressed under the control of HERV-LTR and CAG promoter. In a first model, transgenic mice, generated in a C57Bl6/J background, were challenged by repeated STZ injections. We observed that transgenic mice are more susceptible to pancreatic damage than wild type mice, as they developed more severe insulitis (P<0.0001) and hyperglycemia (P<0.01). In a second model, transgenic mice are currently backcrossed in a NOD/ShiLtJ background. Preliminary results revealed that NOD transgenic males start to develop a hyperglycemia as soon as 4 weeks old compared to their controls littermates. Early results from these transgenic mice support a role for HERV-W-Env in human T1D pathogenesis, particularly in patients expressing this pathogenic protein. They provide additional justification for the ongoing phase IIa clinical trial which is designed to neutralize HERV-W-Env in T1D patients using a monoclonal antibody named GNbAC1 (NCT03179423). Six months interim results of this new therapeutic approach will be available 3rd quarter 2018. Disclosure S. Levet: Employee; Self; Geneuro Innovation. J. Joanou: Employee; Self; Geneuro Innovation. N. Queruel: Employee; Self; Geneuro Innovation. J. Pierquin: Employee; Self; Geneuro Innovation. H.J.F. Perron: Employee; Self; GeNeuro SA.