The goal of immunotherapy research in asthma has been the development of interventions that would specifically affect the pathological immune response without the general immunosuppression induced by steroid therapy. Much of the research on animal models has focused on reagents that can block the induction of allergic immunity, but fail to inhibit secondary Th2-mediated immune responses that are responsible for the inflammation characteristic of asthmatic lungs. A novel costimulatory molecule expressed on activated T cells, ICOS, and its ligand, B7h, were recently identified. ICOS costimulation leads to the induction of Th2 cytokines without augmentation of IL-2 production, suggesting a role for ICOS in Th2 cell differentiation and expansion. During the last grant period, we found that when a soluble form of ICOS, ICOS-Ig, was administered to B6 mice in a Th2 model of airway inflammation throughout the sensitization and challenge phases, attenuation of the inflammation was found. There was a pronounced decrease in cellular infiltration into the lung tissue and airways. These inhibitory effects were not due to a lack of T cell priming nor to a defect in Th2 differentiation. In addition, ICOS/B7h blockade during ex vivo restimulation of lung Th2 effector cells blocked cyotkine production. The central hypothesis of this proposal is that although not required for Th2 differentiation, ICOS-mediated costimulation plays a significant role in regulating Th2-mediated disease upon secondary exposure to antigen. Therefore, the goal of this grant proposal is to characterize mechanisms by which ICOS signaling affects Th2 effector and memory responses during Th2-mediated airway inflammation. To achieve these goals, we propose the following specific aims: number 1: To determine the effect of ICOS-mediated costimulation on memory vs. effector Th2 cell responses. Number 2: Determine the relative contributions of ICOS and CD28 to the induction of Th2-mediated airway inflammation. Number 3: To determine the role of ICOS-mediated costimulation in the regulation of Th2 effector cell migration.
