Celiac disease is an inflammatory autoimmune disease in which CD4+ T cells target, damage and eventually destroy the villous tissue structures of the small intestine, interfering with the absorption of nutrients from food. People who have celiac disease cannot tolerate gluten, a protein found in wheat, rye and barley. This debilitating disease affects 1 of every 120-300 people, which in the United States alone translates to a market size of roughly 2.2 million people. The goal of the proposed work is to test lead compounds (developed under Phase I funding) in vitro on human HLA-DQ-restricted T cell clones, and quantify their ability to control activated intestinal T cells in HLA-DQ transgenic mice. The approach presented is based on patented RTL technology (US Patent #6,270,772) for which Virogenomics holds an exclusive license. The therapeutic efficacy of the RTL technology was first described in EAE (experimental autoimmune encephalomyelitis), an animal model of multiple sclerosis. In this animal model, RTLs inhibited activation of pathogenic T cells and could be used to prevent and treat disease. The potential of these molecules in the treatment of other human diseases provided a strong rationale to develop HLA-DQ-derived human RTLs for treatment of celiac disease. Under Phase I funding, HLA-DQ-derived Recombinant T cell receptor Ligands (RTLs) were designed and purified. These molecules also underwent rigorous biochemical and biophysical characterization. Recently, huCD4/DQ2 and huCD4/DQ8 transgenic mouse models of gluten sensitivity have been developed. In the huCD4/DQ8 transgenic model, the T cell response to gluten was CD4 dependent, HLA-DQ restricted and led to the production of cytokines IL-6, TGF-beta and IL-10, with intestinal lymphocytes from gluten-fed mice displaying an activated phenotype. We will use these animal models to take DQ-derived RTL lead compounds through proof-of-concept experiments in vivo. Under Phase II funding we propose 1) In vitro characterization of the biological effects of DQ-derived RTLs on human T cell lines obtained from patients with celiac disease, using these studies to refine our lead compounds to maximize their biological activity; and 2) Characterization of RTL dosage requirements to modulate cytokine production and block activation of intestinal T cells in transgenic mouse models of celiac disease. ? ? ?
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