Asthma is a major public health issue, and its pathogenesis is complex. In the particular, the role of CC chemokines in this disease is poorly understood. We have successfully developed a new animal model in which antigen (Ag)-pulsed dendritic cells (DC) are able to induce airway hyperreactivity (AHR), goblet cell hyperplasia, specific IgE response, hypereosinophilia, and marked lung inflammation. We have also shown that in mutant mice deficient in CC chemokine receptor 2 (CCR2-/-), an accelerated Th2 response is seen in the lung after aeroallergen challenge. Others and we have shown that CCR2 deficiency alters the migration of monocytes, and possibly other cells, such as Th lymphocytes. In this proposal, the role of MCP-1 in the induction of various pathological changes will be investigated. In addition, altered leukocyte migration, as related to the pathogenesis of asthma, will be studied.
Three specific aims are proposed.
Aim 1 : To demonstrate that elevated MCP- 1 plays a major role in the observed accentuated Th2 response in the lung in the Ag induced asthma model, using either neutralizing anti-MCP-1 antibody 2H5 or CCR2-/-/MCP-/--1 double mutant mice.
Aim 2 : To determine the kinetics of lymphocyte, monocyte and eosinophil migration to the lungs and airways in allergen-challenged CCR2-/- mice. This will be done by studying mice at increasing intervals after onset of Ag-challenge using flow cytometry on total lung leukocytes, or immunohistochemical staining of lung tissue. Antibodies to characterization leukocytes will include F4/80 (macrophage), anti-CD4 mAb, anti-CD8 mAb, Thi (IFNghigh, IL-5low), Th2 (IFNglow, IL-5high), anti-MHC class I mAb (antigen presenting cells), and anti-DEC-205 (DC).
Aim 2 will also evaluate lung trafficking of adoptively transferred Tg+ CD4 cells from CCR2-/- or CCR2+/+ DO 11.10 mice, to address the issue of whether altered numbers of Th subsets in the lung are related to trafficking or in situ differentiation.
Aim 3 : To determine the relative role of monocytes and lymphocytes in the accentuated Th2 response in the allergen-challenged CCR2-/- mice. This will be done using chimeric mice created by adoptive transfer of CCR2+/+ or CCR2-/- Tg+ DO 11.10 CD4 cells into either CCR2+/+ or CCR2-/- nude mice. The expected results will provide further insight into the role of cytokines and chemokines and cellular migration in allergic asthma. This insight may allow us to devise novel therapeutics targeted at a specific molecule or at a specific cell population.
| Rose Jr, C Edward; Lannigan, Joanne A; Kim, Paul et al. (2010) Murine lung eosinophil activation and chemokine production in allergic airway inflammation. Cell Mol Immunol 7:361-74 |
| Sung, Sun-Sang J; Fu, Shu Man; Rose Jr, C Edward et al. (2006) A major lung CD103 (alphaE)-beta7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J Immunol 176:2161-72 |
| Grinnan, Dan; Sung, Sun-Sang; Dougherty, Joseph A et al. (2006) Enhanced allergen-induced airway inflammation in paucity of lymph node T cell (plt) mutant mice. J Allergy Clin Immunol 118:1234-41 |
