Specific blockade of protein kinase C (PKC)-theta with a small molecule antagonist attenuates lung inflammation in a mouse model of established allergic airway disease (140.21)

Abstract

Abstract PKCθ is primarily expressed in T cells and is recruited to the immunological synapse upon T cell receptor signaling. PKCθ deficient mice display a diminished pulmonary inflammatory response following allergen challenge. We investigated the allergic airway response in mice when PKCθ is specifically blocked with a small molecule inhibitor (compound A). Mice were sensitized with ovalbumin (OVA) in alum on days 0 and 14, then challenged with OVA on days 26, 27, and 28 (primary challenges). Four weeks later mice were aerosolized once with OVA (rechallenge). Airway inflammation was monitored after both primary challenges and rechallenge. Compound A was dosed 30 mg/kg intraperitoneally twice daily in 3 dosing regimens: for 4 days concurrent with and after the primary challenges only; for 3 days starting before the OVA rechallenge only; and both of the above regimens. Administration of compound A significantly inhibited the influx of eosinophils, lymphocytes and neutrophils into the airways. Ex vivo antigen induced Th2 cytokine production by splenocytes was also reduced in cells obtained from mice treated with Compound A in either the primary challenge phase, or both primary and rechallenge phases, but not the rechallenge phase alone. We conclude that blocking T cell activation with a PKCθ inhibitor may attenuate airway inflammation in established allergic disease and may be beneficial in treating chronic allergic asthma.