Allergic asthma is characterized by airway hyperreactivity and chronic mucosal inflammation mediated by CD4+ Th2 cells. There is increasing evidence to suggest that the chronic inflammation arises as a consequence of a defect in regulatory mechanisms. Our long-term goal is to elucidate which immunomodulatory events are normally operative to limit allergic airway inflammation mediated by CD4+ T cells. Our work has enabled us to formulate the central hypothesis that """"""""allergic pulmonary inflammation is regulated by the action of PGI2 and CD4+CD25+ regulatory T cells, which cooperate in the suppression of lung mucosal Th2 responses"""""""". We base this hypothesis from studies demonstrating that selective inhibition of COX-2 in vivo specifically reduced PGI2 production and resulted in a concomitant increase in the level of allergic inflammation. The PGI2 receptor (IP-receptor) was induced by IL-4 and predominantly expressed by CD4+CD25+ T regulatory cells. CD4+CD25+ T cells were shown to play a crucial role in regulating Th2-mediated pulmonary inflammation.
3 aims pertaining to key regulatory mechanisms that control allergic inflammation will be investigated. 1. To elucidate the cellular and molecular requirements for the production of the anti-inflammatory prostanoid PGI2 and examine the induction and function of its receptor during lung inflammation. 2. To determine the mechanism by which CD4+CD25+ T regulatory cells suppress allergic pulmonary inflammation and the role of IL-10 and glucocorticoid-induced TNF receptor in modulating this regulation. The role of CD4+CD25+ T cells in suppressing (i) the development of CD4+ Th2 responses, and (ii) effector Th2-mediated inflammatory responses in vivo will be addressed. 3. To resolve the mechanism by which PGI2 and CD25+ T cells cooperate to limit allergic inflammation and the contribution of this form of immune modulation to NSAID-induced exacerbations of asthma.
