Development of citrullinated-vimentin-specific CAR for targeting Tregs to treat autoimmune rheumatoid arthritis

Abstract

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by an aberrant inflammation of the synovial membrane that causes irreversible joint and bone damage. Regulatory T cells (Tregs) are defective in RA patients while adoptive transfer of expanded autologous Tregs efficiently reverse disease in collagen-induced arthritis, an animal model of RA. Moreover, providing an antigen (Ag) specificity to Tregs render them more potent to suppress abnormal inflammation by increasing specific activity and promoting selective migration to the Ag-expressing tissue, reducing the risk of pan-immunosuppression in the meantime. These studies strongly suggest that Treg therapy may be effective in the treatment of RA patients by reducing joint inflammation and inducing immune tolerance and may be improved by using Ag-specific Tregs. Therefore, we aimed to engineer Ag-specific Tregs from polyclonal Tregs using a chimeric antigen receptor (CAR) specifically targeting an Ag present in the joint of RA patients. We generated a CAR directed against a post-translationally modified intermediate filament protein, citrullinated vimentin (CV), an Ag found, abundantly and almost exclusively, in the extracellular matrix of the inflamed synovial tissue of the RA patients. CV-specific CAR was transduced into human Tregs that were efficiently activated, expanding and suppressing following CAR-mediated stimulation. Importantly, CV-CAR Tregs were shown to react with CV expressed in RA patient synovial fluid. Studies are underway to demonstrate the functional activity of these CV-CAR Tregs in in vivo mouse models, a validation step in the development of a promising therapeutic tool to treat RA and potentially other autoimmune disorders.