The long-term objectives of this laboratory are to elucidate the immunopathologic basis of airway obstruction in a murine model of asthma. This proposal will investigate the role the epithelium plays in allergic lung inflammation and focus specifically on two epithelium-derived immunoregulatory molecules, Clara cell secretory protein (CCSP) and syndecan-1. Clara cells are non-ciliated respiratory epithelial cells that secrete one of the most abundant airway proteins, CCSP. The airway epithelium also sheds the heparin sulfate proteoglycan syndecan-1 into the airway. Although the biological functions of CCSP remain unclear, it is an antiprotease potentially capable of neutralizing exogenous proteases, which our laboratory has shown are critical to the induction of allergic airway disease. CCSP may also regulate adaptive immune responses of the airway by influencing epithelium-derived factors necessary for growth and survival of T cells. Our preliminary studies show that both CCSP and syndecan-1 down-regulate airway Th2 responses provoked by exogenous proteases. Thus, CCSP and syndecan-1 are immunosuppressive with regard to allergic lung inflammation, but their precise mechanisms of action remain uncertain.
In Aim 1, we will dissect the major mechanism by which CCSP attenuates allergic inflammation. We will focus specifically on T cell-dependent effects and explore T helper effector differentiation in vitro and in vivo, Th2 homing to lung and Th2 activation and cytokine production in vitro. Where effects are observed, we will correlate immunosuppressive activities with the antiprotease potential of CCSP.
For Aim 2, we will explore the potential of CCSP for prevention/amelioration of allergic lung disease. Mice will be challenged intranasally with CCSP during immune induction with protease-containing allergens and following established allergic lung inflammation to evaluate these two endpoints. Efficacy of CCSP will be compared to a specific protease inhibitor, streptomyces subtilisin inhibitor (SSI). Finally, Aim 3 will explore how syndecan-1 modulates allergic inflammation, either through effects of the core protein or the heparin sulfate side chains. We will extend these mechanistic studies to understand if either CCSP or syndecan-1 directly suppress Th2 function in vitro. Together, our findings will provide broad insight into how the epithelium modulates allergic inflammation, potentially identifying novel therapeutic targets.
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| Knight, John M; Lee, Seung-Hyo; Roberts, Luz et al. (2014) CD11a polymorphisms regulate TH2 cell homing and TH2-related disease. J Allergy Clin Immunol 133:189-97.e1-8 |
| Millien, Valentine Ongeri; Lu, Wen; Shaw, Joanne et al. (2013) Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 341:792-6 |
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| Hong, Jeong-Soo; Greenlee, Kendra J; Pitchumani, Ramanan et al. (2011) Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol 186:6427-36 |
| Porter, Paul C; Ongeri, Valentine; Luong, Amber et al. (2011) Seeking common pathophysiology in asthma, atopy and sinusitis. Trends Immunol 32:43-9 |
| Porter, Paul C; Roberts, Luz; Fields, Anna et al. (2011) Necessary and sufficient role for T helper cells to prevent fungal dissemination in allergic lung disease. Infect Immun 79:4459-71 |
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