The specific goals of this Phase I STTR are to design, manufacture, and characterize a set of therapeutic tools that can control the pathogenic CD4+ T cells that mediate celiac disease. The approach presented is based on patented Recombinant T cell receptor Ligand (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. RTLs inhibited activation of pathogenic T cells and could be used to prevent and treat EAE. The potential of these molecules in the treatment of other human autoimmune diseases provides strong rationale to develop HLADQ- derived human RTLs for treatment of celiac disease. Celiac disease is a 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, and this debilitating disease affects 1 of every 120- 300 people. In the United States alone this translates to a market size of roughly 2.2 million people. To produce and test HLA-DQ-derived RTLs and prepare these therepeutic agents for commercialization, the following specific aims are proposed:
SPECIFIC AIM 1. Production and biophysical characterization of HLA-DQ-derived Recombinant TCR Ligands (""""""""RTLs"""""""").
SPECIFIC AIM 2. Biochemical characterization of the binding interaction of gluten peptides with HLA-DQ derived RTLs.
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| Huan, J; Meza-Romero, R; Mooney, J L et al. (2011) Single-chain recombinant HLA-DQ2.5/peptide molecules block ?2-gliadin-specific pathogenic CD4+ T-cell proliferation and attenuate production of inflammatory cytokines: a potential therapy for celiac disease. Mucosal Immunol 4:112-20 |
| Sinha, Sushmita; Subramanian, Sandhya; Miller, Lisa et al. (2009) Cytokine switch and bystander suppression of autoimmune responses to multiple antigens in experimental autoimmune encephalomyelitis by a single recombinant T-cell receptor ligand. J Neurosci 29:3816-23 |
