O006 Role of nucleic acid-binding polymers in TLR activation and autoimmune disease development

Abstract

Introduction Toll-like receptors (TLRs) play a critical role in innate and adaptive immune responses by responding to pathogenic nucleic acids. Moreover, they have recently been shown to play a role in the pathogenesis of autoimmune disorders such as systemic lupus erythematosus (SLE) due to their ability to recognize self-antigens. There has been growing evidence suggesting that blocking of nucleic acid-sending TLRs such as TLR7 and 9 results in ameliorated disease. Although effective in blocking autoimmune disease progression, TLR inhibitors are not ideal given that they interfere with normal responses to pathogens. Our goal is to create compounds that bind nucleic acids prior to their entry into the cell and engagement of TLRs. Here we determined the role of nucleic acid-binding cationic polymers in neutralizing the proinflammatory effects of nucleic acids on a variety of immune cells implicated in autoimmune disease development. Methods B cells and dendritic cells (DCs) of wild type and lupus prone mice were exposed to TLR7 and 9 synthetic agonists. Supernatants were subsequently assessed for nucleic acid-driven proinflammatory cytokine release, plasma cell differentiation and antibody production. Cells were also assessed for their ability to respond to encapsulated viral particles in the presence of nucleic-acid binding cationic polymers. Results Nucleic acid-binding polymers inhibit TLR activation and subsequent cytokine production by both dendritic cells (DCs) and B cells of wild type and lupus prone mice. They also block nucleic acid-driven plasma cell differentiation and antibody production. Additionally, they modulate co-stimulatory cell surface marker expression (CD80, CD86) in stimulated DCs and B cells. Stimulation of immune cells by encapsulated viral particles is unaffected in the presence of polymers. Conclusion These findings provide a new avenue in drug development as nucleic acid-binding agents can potentially be utilized to block overt autoimmune disorders while allowing normal immune responses to occur.