The relationship between the cytokines TNF and TL1A in rheumatoid arthritis

Abstract

Abstract The TNF-family cytokine TL1A (TNF-like ligand 1A) signaling through its receptor DR3 (Death Receptor 3) promotes immunopathology in diverse autoimmune disease models by facilitating T cell accumulation and Innate Lymphoid Cell activation at the site of inflammation while leaving systemic immune responses unaffected. TNF, a close homolog of TL1A, is a successful therapeutic in autoimmune diseases including rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). However, a significant fraction of patients do not adequately respond to TNF blockade and are in need of alternative therapies. Previous studies have reported elevated TL1A levels in serum and synovial fluid of patients with RA. Yet, how TL1A expression may be influenced by TNF, and whether blocking TL1A/DR3 interactions would be a viable treatment for RA is unknown. We found that soluble TL1A levels are specifically elevated in synovial fluid and serum from RA patients, and that TNF blockade reduces serum TL1A levels in both responders and non-responders. Additionally, in a murine model of collagen-induced arthritis, antibody blockade of TL1A reduced both clinical disease and bone destruction. To further understand the relationship between TL1A and TNF we are now utilizing the TNFDARE mouse model of spontaneous TNF driven arthritis crossed to DR3 deficient mice. By 3D micro CT imaging and cytokine analysis of the joints we will determine if the blockade of TL1A/DR3 interactions alleviates arthritis driven by excess TNF. Taken together, these studies support an investigation into TL1A blockade as a potential therapy for patients with rheumatoid arthritis.