Profound airway inflammation and airway remodeling accompanies responses to the fungus Aspergillus fumigatus, complicating asthma and cystic fibrosis. The introduction of A. fumigatus conidia into the airways of mice previously sensitized to A. fumigatus leads a fungal asthma-like disease characterized by elevated IgE and IgG1, and pulmonary expression of chemokines and Th2 cytokines. These events are also associated with a marked peribronchial accumulation of CD4+ T cells and eosinophils concomitant with marked airway hyperresponsiveness, goblet cell hyperplasia and peribronchial fibrosis. Previously, we have shown that the immunoneutralization of monocyte chemo-attractant protein-1 (MCP-1/CCL2) in A. fumigatus-sensitized mice challenged with conidia leads to aggressive fungal colonization due to a major compromise in the innate immune response. In contrast, we have observed that the immunoneutralization of regulated on T-cell activation, normal T cell expressed and secreted (RANTES/CCL5) does not impair the elimination of A. fumigatus and inhibits the development of chronic fungal asthma. Using this model, we will address the hypothesis that the selective targeting of RANTES/CCL5-responsive cells in the lung abolishes allergic effector and remodeling features of this model without compromising the necessary innate immune responses. This hypothesis will be addressed through the following three Specific Aims: 1) To determine the roles of RANTES/CCL5 in the pulmonary innate immune response against live A. fumigatus conidia. 2) To determine the mechanism through which iRANTES/CCL5 modulates the allergic effector responses mediated by T cells and eosinophils. 3) To determine the mechanism through which RANTES/CCL5 contributes to the persistent airway remodeling features such as goblet cell hyperplasia and peribronchial fibrosis that characterize chronic fungal asthma. These detailed studies are now possible because of the availability of novel chimeric protein that selectively targets RANTES/CCL5-responsive cells in the lung.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069865-04
Application #
7098900
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Noel, Patricia
Project Start
2003-08-15
Project End
2007-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$255,311
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Buckland, Karen F; Ramaprakash, Hemanth; Murray, Lynne A et al. (2011) Triggering receptor expressed on myeloid cells-1 (TREM-1) modulates immune responses to Aspergillus fumigatus during fungal asthma in mice. Immunol Invest 40:692-722
Ramaprakash, Hemanth; Hogaboam, Cory M (2010) Intranasal CpG therapy attenuated experimental fungal asthma in a TLR9-dependent and -independent manner. Int Arch Allergy Immunol 152:98-112
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Joshi, Amrita D; Schaller, Matthew A; Lukacs, Nicholas W et al. (2008) TLR3 modulates immunopathology during a Schistosoma mansoni egg-driven Th2 response in the lung. Eur J Immunol 38:3436-49
Daley, Eleen; Emson, Claire; Guignabert, Christophe et al. (2008) Pulmonary arterial remodeling induced by a Th2 immune response. J Exp Med 205:361-72
Buckland, K F; O'Connor, E; Murray, L A et al. (2008) Toll like receptor-2 modulates both innate and adaptive immune responses during chronic fungal asthma in mice. Inflamm Res 57:379-87
Buckland, Karen F; O'connor, Erica C; Coleman, Eilish M et al. (2007) Remission of chronic fungal asthma in the absence of CCR8. J Allergy Clin Immunol 119:997-1004
Meneghin, Alessia; Hogaboam, Cory M (2007) Infectious disease, the innate immune response, and fibrosis. J Clin Invest 117:530-8

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