vx-770 and Autoimmune-Diseases

Sjögren's syndrome and autoimmune pancreatitis are disorders with decreased function of salivary, lacrimal glands, and the exocrine pancreas. Nonobese diabetic/ShiLTJ mice and mice transduced with the cytokine BMP6 develop Sjögren's syndrome and chronic pancreatitis and MRL/Mp mice are models of autoimmune pancreatitis. Cystic fibrosis transmembrane conductance regulator (CFTR) is a ductal Cl. We treated the mice models with the CFTR corrector C18 and the potentiator VX770. Glandular, ductal, and acinar cells damage, infiltration, immune cells and function were measured in vivo and in isolated duct/acini.. In the disease models, CFTR expression is markedly reduced. The salivary glands and pancreas are inflamed with increased fibrosis and tissue damage. Treatment with VX770 and, in particular, C18 restored salivation, rescued CFTR expression and localization, and nearly eliminated the inflammation and tissue damage. Transgenic overexpression of CFTR exclusively in the duct had similar effects. Most notably, the markedly reduced acinar cell Ca. Our findings reveal that correcting ductal function is sufficient to rescue acinar cell function and suggests that CFTR correctors are strong candidates for the treatment of Sjögren's syndrome and pancreatitis.

Topics: Acinar Cells; Aminophenols; Animals; Aquaporin 5; Autoimmune Diseases; Bone Morphogenetic Protein 6; Calcium Signaling; Chloride Channel Agonists; Cyclopropanes; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Female; Genetic Therapy; Inositol 1,4,5-Trisphosphate Receptors; Mice, Inbred MRL lpr; Mice, Inbred NOD; ORAI1 Protein; Pancreas; Pancreatitis; Quinolones; Recovery of Function; Salivary Glands; Salivation; Sjogren's Syndrome; Time Factors; Tissue Culture Techniques; Transduction, Genetic; Up-Regulation