Asthma is a disease characterized by reversible airflow obstruction and bronchial inflammation. There is considerable evidence in human and murine models of asthma that CD4 T cells and in particular IL-4 and IL-5 secreting Th2 cells are associated with the characteristic airway response. The goals of this proposal are 1) to understand the role of committed Th1 and Th2 effector CD4 T cells in eliciting airway inflammation and bronchial hyperresponsiveness focussing on characterizing the unique pathology induced by each type of effector T cell and 2) to determine if the interaction between Th1 and Th2 cells in the airway is synergistic or antagonistic in the induction of airway events. To understand how the pathology associated with asthma can be elicited and regulated by activated CD4 T cells, we will take advantage of an established cell transfer system in which antigen-specific, committed Th1 cells, Th2 cells or both, derived from mice transgenic for a known T cell receptor, are transferred into naive mice and are recruited and activated in the airway by inhaled antigen. The role of Th1 and Th2 effector cells in inhibiting or exacerbating airway inflammation and hyperresponsiveness will be examined by 1) characterizing the effect of transferring either primed Th1 or Th2 CD4 effector T cells on airway events, 2) determining the role of Th2/Th1 cytokines and cytokine responsive cells in the generation of airway inflammation and AHR using cytokine/cytokine receptor deficient mice, and 3) determining the effect of Th1: Th2 interaction of the airway microenvironment on modulating the airway response elicited by a particular subset of CD4 T cell. From these studies we hope to gain an understanding of the role of Th1 and Th2 cells in eliciting a pathology characteristic of human asthma and to investigate methods to abrogate an ongoing, committed CD4 effector T cell response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL056389-04
Application #
6302433
Study Section
Project Start
1999-12-01
Project End
2000-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
4
Fiscal Year
2000
Total Cost
$186,979
Indirect Cost
Name
Yale University
Department
Type
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Liu, Juan; Harberts, Erin; Tammaro, Antonella et al. (2014) IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis. J Invest Dermatol 134:1903-1911
Bhandari, Vineet; Choo-Wing, Rayman; Harijith, Anantha et al. (2012) Increased hyperoxia-induced lung injury in nitric oxide synthase 2 null mice is mediated via angiopoietin 2. Am J Respir Cell Mol Biol 46:668-76
Homer, Robert J; Elias, Jack A; Lee, Chun Gun et al. (2011) Modern concepts on the role of inflammation in pulmonary fibrosis. Arch Pathol Lab Med 135:780-8
Koh, Byung Hee; Hwang, Soo Seok; Kim, Joo Young et al. (2010) Th2 LCR is essential for regulation of Th2 cytokine genes and for pathogenesis of allergic asthma. Proc Natl Acad Sci U S A 107:10614-9
Chapoval, Svetlana P; Lee, Chun Geun; Tang, Chuyan et al. (2009) Lung vascular endothelial growth factor expression induces local myeloid dendritic cell activation. Clin Immunol 132:371-84
Pillemer, Brendan B L; Xu, Hui; Oriss, Timothy B et al. (2007) Deficient SOCS3 expression in CD4+CD25+FoxP3+ regulatory T cells and SOCS3-mediated suppression of Treg function. Eur J Immunol 37:2082-9
Ostroukhova, Marina; Qi, Zengbiao; Oriss, Timothy B et al. (2006) Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. J Clin Invest 116:996-1004
Ostroukhova, Marina; Seguin-Devaux, Carole; Oriss, Timothy B et al. (2004) Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J Clin Invest 114:28-38
Lee, Gap Ryol; Flavell, Richard A (2004) Transgenic mice which overproduce Th2 cytokines develop spontaneous atopic dermatitis and asthma. Int Immunol 16:1155-60
Ma, Bing; Zhu, Zhou; Homer, Robert J et al. (2004) The C10/CCL6 chemokine and CCR1 play critical roles in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol 172:1872-81

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