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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079189-01A1
Application #
6969960
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Noel, Patricia
Project Start
2005-07-05
Project End
2010-06-30
Budget Start
2005-07-05
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$313,903
Indirect Cost
Name
University of Montana
Department
Other Health Professions
Type
Schools of Pharmacy
DUNS #
010379790
City
Missoula
State
MT
Country
United States
Zip Code
59812
Simons, Bryan; Ferrini, Maria E; Carvalho, Sophia et al. (2017) PGI2 Controls Pulmonary NK Cells That Prevent Airway Sensitization to House Dust Mite Allergen. J Immunol 198:461-471
Ferrini, Maria; Carvalho, Sophia; Cho, Yoon Hee et al. (2017) Prenatal tobacco smoke exposure predisposes offspring mice to exacerbated allergic airway inflammation associated with altered innate effector function. Part Fibre Toxicol 14:30
Jaffar, Zeina; Ferrini, Maria E; Shaw, Pamela K et al. (2011) Prostaglandin I?promotes the development of IL-17-producing ?? T cells that associate with the epithelium during allergic lung inflammation. J Immunol 187:5380-91
Girtsman, Teri; Jaffar, Zeina; Ferrini, Maria et al. (2010) Natural Foxp3(+) regulatory T cells inhibit Th2 polarization but are biased toward suppression of Th17-driven lung inflammation. J Leukoc Biol 88:537-46
Leyva, Francisco J; Roberts, Kevan (2010) Crocidolite induces prostaglandin I(2) release mediated by vitronectin receptor and cyclooxygenase-2 in lung cells. Lung 188:133-41
Jaffar, Zeina; Ferrini, Maria E; Herritt, Lou A et al. (2009) Cutting edge: lung mucosal Th17-mediated responses induce polymeric Ig receptor expression by the airway epithelium and elevate secretory IgA levels. J Immunol 182:4507-11
Jaffar, Zeina; Ferrini, Maria E; Girtsman, Teri A et al. (2009) Antigen-specific Treg regulate Th17-mediated lung neutrophilic inflammation, B-cell recruitment and polymeric IgA and IgM levels in the airways. Eur J Immunol 39:3307-14
Jaffar, Zeina; Ferrini, Maria E; Buford, Mary C et al. (2007) Prostaglandin I2-IP signaling blocks allergic pulmonary inflammation by preventing recruitment of CD4+ Th2 cells into the airways in a mouse model of asthma. J Immunol 179:6193-203