Combination blockade of OX40L and CD30L inhibits allergen-driven memory TH2 cell reactivity and lung inflammation

Background: The selective reduction of memory T(H)2 cell responses could be key to affording tolerance and protection from the recurrence of damaging allergic pathology. Objective: We asked whether TNF family costimulatory molecules cooperated to promote accumulation and reactivity of effector memory CD4 T cells to inhaled complex allergen, and whether their neutralization could promote airway tolerance to subsequent reexposure to allergen. Methods: Mice were sensitized intraperitoneally or intranasally with house dust mite and challenged with intranasal allergen after memory had developed. We assessed whether single or combined blockade of OX40L/CD252 and CD30L/CD153 inhibited memory T cells from driving acute asthmatic lung inflammation and protected mice following exposure to allergen at a later time. Results: OX40- or CD30-deficient animals showed strong or partial protection against allergic airway inflammation; however, neutralizing either molecule alone during the secondary response to allergen had little effect on the frequency of effector memory CD4 T cells formed and acute lung inflammation. In contrast, a significant reduction in eosinophilic inflammation was observed when OX40L and CD30L were simultaneously neutralized, with dual blockade inhibiting effector memory T(H)2 cell expansion in the lungs, whereas formation of peripherally induced regulatory T cells remained intact. Moreover, dual blockade during the secondary response resulted in a tolerogenic state such that mice did not develop a normal tertiary memory T(H)2 cell and lung inflammatory response when challenged weeks later with allergen. Conclusion: Memory T-cell responses to complex allergens are controlled by several TNF costimulatory interactions, and their combination targeting might represent a strategy to reduce the severity of inflammatory reactions following reexposure to allergen.