In this project we will investigate a novel application of an immune stimulating agent. Ligands for the Toll-like receptors (TLR) stimulate the innate immune system. However, we are using an agonist to stimulate the cells to create a trap for downstream signaling molecules to reduce their ability to transmit signals from other activating cell surface receptors. Although using an agonist to diminish signaling is counter-intuitive, this innovative approach desensitizes the immune system and limits the inflammatory response. We have chosen to use a TLR7 agonist, as TLR7 is intracellular, and ligands must permeate the cell for activity. It is yet undetermined if there will be feedback reduction in the adaptive immune response. Given this rationale we feel that using an agonist for the innate immune system rather than a defined antagonist is a unique and innovative approach. The central hypothesis of this application is that an orally available TLR7 analog will protect the joint from immune mediated damage. This hypothesis will be tested with the following specific aims: 1. Evaluate the relative potency of TLR desensitization with two orally available TLR7 analogs in two murine models of inflammatory arthritis, 2. Assess the relative roles of innate and adaptive immune cells for TLR hyposensitization with TLR7 agonists in T cell independent model of arthritis, and 3: Assess the effect of oral TLR hyposensitization on adaptive immune responses. We have assembled a team of investigators with complementary expertise in medicinal chemistry (Cottam), murine models of inflammatory disease (Corr), and innate immunity (Hayashi) within an academic setting. The combined efforts of these investigators will be able to more rapidly integrate the phases of the project than any single one could independently. Drs. Cottam, Corr and Hayashi are long standing collaborators and have been working together to investigate the mechanisms of adenine and guanine analogs that exhibit biologic properties of potential clinical application. The compounds will be generated in Dr. Cottam's laboratory and analyzed for purity. Drs. Corr and Hayashi will be responsible for the in vitro and in vivo testing for oral and systemic potency in early and established disease. In the long term the results of these investigations might lead to additions in our therapeutic armamentarium to reduce the inflammatory damage from autoimmune disease.
Although there are several biologic agents that treat rheumatoid arthritis none are universally effective, This project will examine the beneficial immunomodulatory effects of a novel second generation Toll- like receptor agonist that is orally available.
