Therapeutic Inhibition of BCL6 in Systemic Lupus Erythematosus

ABSTRACT Systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are characterized by polyclonal T cell activation driving the production of pathogenic class switched autoantibodiesThe class switchedsomatically mutated antibodies are generated from germinal centerGCB cellsA subset of effector CDT cellsknown as T follicular helperTfhcellshas been shown to play an integral role in production of antibodies by GC B cellsThe importance of Tfh cells in lupus pathogenesis is understood by the increased numbers of Tfh cells observed in lymphoid organs in murine lupusand the presence of Tfh cells found circulating in the blood of human lupus patientsTfh cell secreted cytokines and their soluble factors control the overall dynamics of the GC reactionThe unique roles that Tfh cells have in the GC reaction and the importance of this process in forming pathogenic autoantibodies links these cells to the pathogenesis of systemic autoimmunityTfh and GC B cells require the transcriptional regulator protein B cell lymphomaBCLfor their development and functionIn micegenetic deletion of BCLabolishes Tfh and GC B cell development with a corresponding ablation of the germinal center responseA previously developed small molecule BCLinhibitor administered during a primary immunization in mice has shown the ability to inhibit GC B cell developmentThe initial focus of our study will be to utilize novel small molecule BCLinhibitors to inhibit Tfh and GC B cell responsesAimand ameliorate disease pathology in murine lupusAimWe will analyze Tfh and GC B cells in treated and control mice using flow cytometry and confocal microscopyWe will examine the generation of autoantibodies by ELISAs and assess kidney disease with Handamp E stainingand measure proteinuria after the treatment with our inhibitorsWe will also examine efficacy of our new inhibitors compared to other newly developed BCLinhibitorsBCLregulation is essential for the generation and function of Tfh and GC B cells in lupusThuswe plan to validate our small molecule inhibitors of BCLas potential pharmacological agents for lupusA successful Phase I project will reveal new and effective lupus therapeutic strategies and provide novel BCLinhibitors for Phase II medicinal chemistry to optimize efficacy and drug like propertiesThe long term project goal is to develop a novel targeted therapy to significantly improve treatment of lupus patients NARRATIVE The manipulation of molecules that define T cell and B cell populations will have functional consequences in progression of disease and disease enhancing antibodiesThis study explores regulation of these cells by the BCLprotein as a new target for future therapeutics in autoimmunity