Identifying and Targeting Autoantigen Specific B cells in ANCA Vasculitis

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Abstract

PROJECT SUMMARY I am an Assistant Professor at the University of North Carolina-Chapel Hill (UNC) School of Medicine and part of the UNC Kidney Center. I am a clinician and researcher taking care of patients with autoimmune kidney diseases with a specific interest in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. The current treatment paradigm for ANCA vasculitis includes prolonged courses of immunosuppression. This approach is effective but is associated with long term complications such as infections and malignancy. There is an established cohort of patients with ANCA vasculitis enrolled in our registry. A subset of patients discontinue therapy and remain off treatment without relapse, termed Long-Term Remission Off Therapy (LTROT). These patients have been off therapy for at least 12 months and we have shown return of B cells. However little is understood about the autoantigen specific B cells in long term remission off therapy or differences in BCRs which indicate tolerogenic vs. pathogenic clonal populations. The first research aim is to define immunological remission in terms of the underlying BCRs and the immunophenotype of autoantigen specific B cells in the context of total B cell population. My goal is to identify markers of long-term immunological remission which can be validated in future studies as a clinical tool. The second research aim is to develop therapies to remove autoantigen specific B cells as a proof of concept study for future pre-clinical studies. My central goal is to build innovative clinical tools which can minimize immunosuppression for patients with ANCA vasculitis. I have developed a comprehensive career development plan integrating mentoring and training activities with basic and translational research. My mentorship team includes Dr. Ronald Falk, a world-renowned physician- scientist expert in ANCA vasculitis and co-mentor Dr. Benjamin Vincent, who will mentor me in translational immunogenetics training. My advisory team includes an ANCA B cell expert and a nanoparticle formulation advisor. I will train to develop nanoparticles as a selective therapy for autoantigen specific B cells. My training will focus on lab-based research training supplemented by formal training activities including coursework, national workshops, participation in national and international meetings, as well as instruction in scientific communication and academic leadership. The focus of my training is on immunology, immunogenetics, and nanoparticle drug development. My research aims and career development are supported by a world-class environment at UNC which offers ample resources for junior faculty, including an established vasculitis clinic with dedicated research coordinators for patient recruitment. My translational aims are to define long term remission in the context of B cells and develop targeted nanoparticle therapy for ANCA vasculitis. My proposed K08 research aims, mentorship team, career development plan, and collaborative research environment will catalyze my scientific productivity and provide me with the necessary training to become an independent investigator.