A new T cell lineage (termed Thl7 cells) is characterized by the ability of these lymphocytes to secrete high levels of the proinflammatory cytokine interleukin-17 (IL-17). Murine Thl7 cells play critical roles in many different models of autoimmunity, and the differentiation pathways leading to their production have been characterized extensively in mice. In stark contrast, the role of Thl7 cells in human autoimmune diseases is largely unknown, and only recently have we and others identified the soluble factors that drive Thl7 differentiation in cells derived from healthy humans. In this proposal we will determine if the murine Thl7 paradigm translates into human autoimmunity. We will test the hypothesis that defects in Thl7 cell number, function and differentiation underly a subset of human autoimmune diseases, and that targeting these cell types with anti-IL-17 monoclonal antibodies (mAbs) and other lymphocyte-targeted interventions will be effective in the clinic. We will apply three technology platforms developed at Stanford (autoantigen microarrays, phosphoflow cytometry, and HIT, High Throughput Immunophenotyping using Transcription), as well as multiplexed cytokine/chemokine assays, fluorescence activated cell sorting (FACS), and immunohistochemistry to characterize these cell lineages. There are 4 specific aims of this proposal: (i.) to test the hypothesis that interleukin-21 (IL-21) is required for human Thl7 differentiation;(ii.) to identify novel cell surface markers that further define Thl7 cells in order to purify viable cells for functional studies;(iii.) to characterize the number and function of effector Thl7 and Thl cells, and regulatory T cells (Tregs), in blood and inflamed tissue derived from patients with a variety of systemic autoimmune diseases;and (iv.) to perform mechanistic studies in human patients enrolled in ACE-funded clinical trials of multiple autoimmune diseases treated with existing or emerging biologic agents. The proposed studies will provide new mechanistic insights into human autoimmunity, and will develop and disseminate new reagents and multiplexed assay platforms for use by other ACE investigators.
This Translational Research Project will explore human Th17 cell biology in multiple autoimmune diseases that encompass disciplines including rheumatology, dermatology, pulmonology, and others. New reagents will be created for use by other ACE investigators, novel methods will be disseminated to participating ACE sites, and mechanistic studies will be performed on samples in ACE-funded clinical trials.
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