MICA: Interleukin-21 in rheumatoid arthritis: exploring its therapeutic potential for the development of a novel targeted biologic therapy.

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Rheumatoid arthritis (RA) is a chronic, autoimmune disease that affects ~1% of the population and an important cause of disability and premature mortality. The disease is driven by chronic inflammation of the joint synovial tissue in which there is accumulation of activated immune cells (macrophages, dendritic cells, T-cells, B-cells and plasma-cells). The therapeutic benefit of B-cell depletion with anti-CD20 mAb in RA demonstrated that autoreactive B-cells play a crucial pathogenic role. Likewise, blockade of inflammatory cytokines (TNFa, IL-6) results in significant clinical response. However, ~30-40% of patients remain refractory to current therapies. Thus, the development of better therapies in this area of unmet need remains of critical importance particularly in "resistant" patients where the identification of additional/alternative inflammatory pathways may lead to novel therapeutics. IL-21 is a potent pleiotropic cytokine involved in the activation/differentiation of many immune cell types including B and T cells but also stromal cells with the induction of metalloproteinases and inflammatory cytokines including TNFa. IL-21 is a member of the common cytokine receptor gamma chain-binding family and is mainly produced by activated T-cells including Th17 cells and TFh. TFh play a fundamental role in B cell activation and antibody production in secondary lymphoid organs and control humoral immune responses.IL-21 has been associated with RA based on genetic studies and increased expression in RA patients; however its pathogenic function in RA joints and its potential as a therapeutic target have not been fully addressed. Blockade of IL-21 receptor (IL-21R) considerably ameliorates disease progression in animal models of RA indicating that modulation of the IL-21/IL-21R pathway is a promising therapeutic approach. In support of this application we studied a large cohort of RA patients and demonstrated that i) the IL-21/IL-21R pathway is highly increased in a subset of RA patients presenting focal lesions called ectopic lymphoid structures (ELS) but not in patients with diffuse synovitis; ii) synovial IL-21 protein is expressed in strict association with a subset of TFh-like cells; iii) RA synovial fibroblasts, but not RA dermal fibroblasts, express high levels of IL-21R suggesting that IL-21 acts not only on infiltrating immune cells but also on resident synovial cells; iv) IL-21 and IL-21R expression is maintained for several weeks when RA synovial tissue is engrafted into immunodeficient (SCID) mice and support the production of human autoantibodies. Thus, we ultimately aim to develop effective IL-21 targeting strategies in RA through the following 4 steps: Step 1) Identification of the cellular sources and targets of IL-21 within the joints of RA patients. Step 2) Analysis of IL-21 function on immune and stromal cells isolated from the RA joints in vitro and in vivo in the RA/SCID model. Step 3) Testing IL21/IL21R blocking reagents for human use (in preclinical development with the industrial partner) in the human RA/SCID model. Step 4) Evaluating IL-21 contribution to disease outcome and response to existing traditional and biological therapies in patients with early arthritis and in those treated with anti-TNFa or anti-IL-6R Biologics.By addressing key aspects of IL-21 biology in RA this proposal will advance our knowledge of the role of IL-21 in chronic inflammation, B cell autoimmunity and ELS function with important implications for other autoimmune/chronic inflammatory diseases. Proof of concept studies of the effectiveness of human IL-21 blocking reagents on synovial inflammation and humoral autoimmunity in diseased tissue will advance the development of novel IL-21 therapeutics for the treatment of RA. Finally, the patient-based studies may enable better identification of key responders of IL-21 mediated arthritis and have a means of stratifying subjects in early clinical trials.