Dual Blockade of OX40 and CD30 Signaling Reduces Memory Th2-driven Lung Inflammatory Responses to House Dust Mite Allergen

Abstract

Abstract Allergic asthma is an inflammatory disease that is induced by immune responses to airborne allergens in the lungs. Several studies have identified T cells as being important players in asthma, with Type 2 helper T cells (Th2) being a critical subset. The selective removal of pre-existing pathogenic memory Th2 cells could be a key process leading to enhanced tolerance. We have attempted to identify signaling molecules in the TNF superfamily that regulate memory Th2 cells in a house dust mite (HDM) model of allergic lung inflammation. C57BL/6J mice up-regulated OX40L to higher levels than other TNF family members measured in the lungs in response to HDM exposure. We then tested whether OX40-OX40L interactions were required for memory Th2 cell responses driven by HDM. While OX40-deficient mice displayed strongly reduced overall lung inflammation and Th2 development when challenged with HDM, therapeutic blocking of OX40L at the time of memory T cell reactivation did not result in similar inhibition of allergic responses, implying OX40L may have been important for initiation but not the memory response. Similar negative results were gained by targeting another TNF superfamily protein, CD30L, that was also up-regulated by HDM exposure. However, we observed significant reduction in airway inflammation when OX40L was simultaneously neutralized with CD30L. Dual blockade was found to target memory Th2 cell expansion and effector function but did not prevent accumulation of pTreg cells. This suggests that persisting memory responses to complex allergens are controlled by several co-stimulatory interactions, and only abrogation of signaling through multiple TNF superfamily members might promote airway tolerance.