There is a direct association between type 2 T-lymphocyte profiles and allergic airway inflammation in asthma. One strategy for preventing type 2 responses to an allergen is to suppress the pro-allergic signals that antigen presenting cells (APCs) send to T-cells. The most potent APCs in the lung are dendritic cells (DCs), and recent studies have revealed phenotypic variability in this population, which can strongly polarize the developing T cells. FLT3 Ligand (FL) is a growth factor for DCs, and induces a type 1 T-cell response. We recently reported that FL prevented ovalbumin-induced allergic airway inflammation in mice and suppressed late allergic response (LAR) and airway hyperresponsiveness (AHR). Based on these studies, we developed the hypothesis that FL has therapeutic activity for hosts with asthma by the expansion of DC1 cells, production of IL-12 and induction of a type 1 T cell response that inhibits type 2 T-cell stimulation important in asthma.
In Specific Aim 1, we will examine the ability of FL to reverse LAR, AHR, and eosinophilia in a mouse model of allergic airway inflammation and augment an antigen-specific, type 1T cell response to the inciting allergen. We will determine the dose-response for FL therapeutic activity and duration of effect. We will also examine the effect of FL on clinical correlates of asthma including baseline AHR in mice sensitized, but not challenged with the allergen. Further, we will examine the levels and isotype of antibodies to the allergen and cytokine levels in serum and lung washings, in addition to non-antigen and antigen-specific type 1 and 2 T cell responses by Elispot assays both systemically (spleen) and regionally (mediastinal lymph nodes and collagenase digested lungs). Non-specific therapeutic effect of FL will be examined in Schistoma mansoni-induced allergic airway inflammation model.
In Specific Aim 2, we will investigate the ability of FL to reverse the airway remodeling associated with chronic asthma. We will study the ability of FL to reverse the histopathologic changes, including tracheal and bronchial epithelial thickness and sub-epithelial fibrosis, measure pro-fibrotic cytokines and chemokines and examine smooth muscle hyperplasia.
In Specific Aim 3, we will study the mechanisms of FL therapeutic activity for acute and chronic asthma. We will determine the therapeutic activity of FL in wild type and IL-12( knock-out (KO) mice. As KO mice may have pre-existing compensatory mechanisms, we will also undertake studies examining the therapeutic activity of FL in animals given neutralizing antibodies to IL-12 during allergic airway inflammation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL070885-01A2
Application #
6731425
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Noel, Patricia
Project Start
2004-03-15
Project End
2008-02-28
Budget Start
2004-03-15
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$267,042
Indirect Cost
Name
Creighton University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Hall, Sannette C; Agrawal, Devendra K (2016) Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation. Expert Rev Respir Med 10:171-84
Hall, Sannette C; Fischer, Kimberly D; Agrawal, Devendra K (2016) The impact of vitamin D on asthmatic human airway smooth muscle. Expert Rev Respir Med 10:127-35
Shao, Zhifei; Gaurav, Rohit; Agrawal, Devendra K (2015) Intermediate-conductance calcium-activated potassium channel KCa3.1 and chloride channel modulate chemokine ligand (CCL19/CCL21)-induced migration of dendritic cells. Transl Res 166:89-102
Hall, Sannette; Agrawal, Devendra K (2014) Key mediators in the immunopathogenesis of allergic asthma. Int Immunopharmacol 23:316-29
Gaurav, Rohit; Bewtra, Againdra K; Agrawal, Devendra K (2014) Novel CLC3 transcript variants in blood eosinophils and increased CLC3 expression in nasal lavage and blood eosinophils of asthmatics. Immun Inflamm Dis 2:205-13
Agrawal, Tanupriya; Gupta, Gaurav K; Agrawal, Devendra K (2012) Calcitriol decreases expression of importin ?3 and attenuates RelA translocation in human bronchial smooth muscle cells. J Clin Immunol 32:1093-103
McGee, Halvor S; Stallworth, Arthur L; Agrawal, Tanupriya et al. (2010) Fms-like tyrosine kinase 3 ligand decreases T helper type 17 cells and suppressors of cytokine signaling proteins in the lung of house dust mite-sensitized and -challenged mice. Am J Respir Cell Mol Biol 43:520-9
Agrawal, Devendra K; Shao, Zhifei (2010) Pathogenesis of allergic airway inflammation. Curr Allergy Asthma Rep 10:39-48
McGee, Halvor S; Edwan, Jehad H; Agrawal, Devendra K (2010) Flt3-L increases CD4+CD25+Foxp3+ICOS+ cells in the lungs of cockroach-sensitized and -challenged mice. Am J Respir Cell Mol Biol 42:331-40
McGee, Halvor S; Yagita, Hideo; Shao, Zhifei et al. (2010) Programmed Death-1 antibody blocks therapeutic effects of T-regulatory cells in cockroach antigen-induced allergic asthma. Am J Respir Cell Mol Biol 43:432-42

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