The power of translational investigation has been exemplified by the Massachusetts General Hospital (MGH) Rheumatology/Ragon Institute research group. The group is comprised of clinical investigators from the MGH Rheumatology Division and basic scientists at the Ragon Institute of the MGH, MIT, and Harvard. Both IgG4-related disease (IgG4-RD) and giant cell arteritis (GCA) have been major clinical interests. We have described many of the clinical, pathological, and treatment characteristics of IgG4-RD and developed instruments to facilitate its study. We have also developed a detailed pathophysiological model and identified SLAM-F7 as a marker expressed on cells critical to IgG4-RD pathophysiology: a CD4+ cytotoxic T cell (CTL) and several types of B cells. We have phenotyped this CD4+CTL and the B cells with which it interacts, building a powerful case for the efficacy of an anti-SLAMF7 approach to treatment. Elotuzumab, approved in multiple myeloma, is a humanized monoclonal antibody that targets SLAM-F7. The Primary Clinical Project is a clinical trial program of elotuzumab in IgG4-RD, linked to robust mechanistic studies. Parallel with this work, we have led a worldwide trial of interleukin-6 receptor (IL6R) blockade in GCA that resulted in the worldwide approval of tocilizumab for that disease. Basic studies performed in our laboratories have demonstrated that GCA patients have an expanded population of inflammatory regulatory CD4+ T cells (Tregs) in their blood. These cells express markers of effector CD4+ T cells, produce IL-17, and carry a hypofunctional variant of the master regulatory factor Foxp3. The Alternate Clinical Project is a multi- center, two-arm, randomized, open-label clinical trial that will evaluate the efficacy and safety of IL-6 receptor blockade maintenance versus discontinuation in GCA. Patients will be followed longitudinally with careful clinical assessments to detect disease flares and capture clinical samples at the time of these events. We will investigate the roles of Tregs and other T cell subsets in both peripheral blood and at sites of disease. The Collaborative Project is based on substantial preliminary work that supports a new model for human autoimmune fibrosis. Quantitative multi-color in situ data implicate the clonally-expanded CD4+CTLs originally described by our group in IgG4-RD as the drivers of both IgG4-RD and systemic sclerosis. These CD4+CTLs infiltrate fibrotic tissues, secrete IL-1? and TGF-?, and induce apoptotic death and overly- exuberant tissue remodeling. CD163+ MerTK+ macrophages, generally induced in the context of apoptosis, accumulate in IgG4-RD lesions, indirectly suggesting that T cell-induced apoptotic cell death precedes tissue remodeling in human model of autoimmune fibrosis. Efforts in this proposed ACE program will be facilitated by: 1) a well-organized and already highly- functional ACE Core; and, 2) the MGH Translational Medicine Group, an academic clinical research organization unique to MGH that comprises the ACE Funds Management Core.
This proposed Autoimmunity Center of Excellence, comprised of the Massachusetts General Hospital Rheumatology Division and the Ragon Institute, highlights the power of translational research that can occur when thoughtful and engaged clinical investigators team effectively with innovative basic researchers. Because IgG4-related disease (IgG4-RD) and giant cell arteritis (GCA) are fundamentally different conditions with regard to pace of disease and urgency of treatment, the designs of the Primary and Alternate Clinical Projects are geared to reflect these differences, underscoring the depth of clinical understanding that our group has for these conditions. The Collaborative Project, based on work from our group that delineates a new human model of autoimmune fibrosis, points the way to new therapies for fibrosis in multiple diseases.
