During the past decade, major advances have been made in our understanding of the pathogenesis of autoimmune diseases. While the etiological factors that trigger the diseases vary, development of autoimmune diseases requires coordinated expression of a unique class of genes called inflammatory genes. Inhibiting the functions of this class of genes is effective for ameliorating autoimmune diseases. However, because autoimmune diseases are mediated by many, if not all, inflammatory genes, inhibiting one or a few of them have only limited efficacies. This application is inspired by two lines of recent discoveries: (I) in humans, several genome-wide association studies independently established that c-Rel is a risk factor for six autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS), and (II) in mice, c-Rel deficiency renders them resistant to autoimmune arthritis, encephalomyelitis, colitis, and diabetes. We therefore reasoned that c-Rel is both a risk and pathogenic factor for human autoimmune diseases and that drugs targeting it should be effective for treating the diseases. To test this theory, we have identified two classes of small molecules that specifically inhibit c- Rel function by preventing its binding to DNA. Preliminary studies in mice indicate that these compounds are highly effective in diminishing the severity of ongoing experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. However, most of our knowledge about c-Rel function came from animal studies; the roles of c-Rel in humans are poor understood. Additionally, c-Rel is expressed at high levels by both inflammatory cells and anti-inflammatory regulatory T (Treg) cells; the consequence of pharmaceutical c-Rel inhibition in different cell types is not clear. The goal of this exploratory R21 application is to test the hypothesis that human c-Rel is active in both inflammatory and anti-inflammatory cells and that inhibiting c-Rel in both cell types is required for curing autoimmune diseases.
Information generated from these studies will not only advance our understanding of the c-Rel biology in MS and RA, but also aid in developing novel c-Rel blocking drugs for the treatment of inflammatory diseases. Therefore, this project should advance both scientific knowledge and clinical practice.
