Current paradigms for the treatment of Rheumatoid Arthritis (RA) are inadequate. They do not address the root cause of the disease - aberrant immune reactions that are intiated by dendritic cell (DC) presenation of modified self antigens. To address this, we are developing a multi-component, microparticle-based ‘anti-vaccine’ using biodegradable materials with encapsulated factors. In combination, this MP formulation provides antigen delivery to DCs, and controlled-release of DC recruitment and tolerance-promoting factors to create an immune-modulating microenvironment localized subcutaneously, in which antigen-specific, tolergenic DCs can be generated. Specifically, we have developed poly (lactide-co-glycolide) (PLGA) microparticles (MPs) encapsulating immunomodulatory agents (vitamin D3, transforming growth factor-beta 1, and granulocyte macrophage colony-stimulating factor) and denatured auto-antigen, collagen (for collagen-induced arthritis [CIA] model). We have demonstrated, in vitro, the ability of our MP formulation to induce suppressive DCs, which subsequently inhibit allogenic T-cell proliferation and induce regulatory, FoxP3-expressing T-cells in a MLR. Administration of this MP system to CIA mice also proved to be therapeutically beneficial based a marked decrease in clinical scores of MP-treated mice in comparison to an untreated cohort. Additional metrics that support the therapeutic efficacy of this particulate system include: a) histological analysis - which showed decreased cellular infiltration of the synovium of joints taken from MP-treated mice; b) fFDG PET analysis - demonstrated decrease in PET intensity in joints (relative measure of inflammation) of MP-treated groups compared to control groups; and c) RT-PCR analysis of the cytokines which showed increased expression of anti-inflammatory cytokines (IL-10/ TGF-β1) compared to controls.
University of California, Davis