Eosinophil Functions in the Development of Allergic Asthma
Open Access
- Author:
- Walsh, Elizabeth Rose
- Graduate Program:
- Pathobiology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 12, 2009
- Committee Members:
- Avery August, Dissertation Advisor/Co-Advisor
Avery August, Committee Member
Margherita Teresa Anna Cantorna, Committee Member
Zhi Chun Lai, Committee Member
Andrea Marie Mastro, Committee Member
Pamela Hankey, Committee Chair/Co-Chair - Keywords:
- allergic
asthma
eosinophil
T cell
Th2 - Abstract:
- Eosinophils have been implicated as playing a major role in allergic airway responses. However, the importance of these cells to the development of this disease has remained ambiguous despite many studies, partly due to lack of appropriate model systems. Here, using transgenic murine models, we clearly delineate a role for eosinophils in asthma. We report that there are strain specific differences in the generation of allergic asthma in eosinophil-deficient ΔdblGATA mice, and that eosinophils are required for development of this disease on the C57Bl/6 background, but not the Balb/c background. This defect was due to reduced chemokine production in the lungs, defective T cell recruitment to lungs, and subsequent Th2 cytokine production. We found that adding WT eosinophils or chemokines back to the lungs of these mice could restore all of these processes, suggesting that eosinophils provide a signal integral to the initiation of the allergic response. The signal that eosinophils provide to induce the recruitment of T cells to the lung during an allergic response is unclear, but other studies and this research show that eosinophils contain preformed message for the cytokine IL-13. Thus, we wanted to determine how eosinophil production of this cytokine contributes to allergic asthma. We were able to rescue symptoms of allergic asthma, such as airway hyperresponsiveness (AHR) and Th2 cytokine production when we administered IL-13 back to the lungs of C57Bl/6 ΔdblGATA mice. We also found that eosinophils deficient in this cytokine were unable to rescue AHR, T cell recruitment to the lungs, and Th2 cytokine/chemokine production in ΔdblGATA mice, even if Th2 cells were added back with IL-13-/- eosinophils. However, eosinophil-derived IL-13 was not able to rescue an allergic asthma response in the absence of IL-13-competent T cells in IL-13-/-mice, although increased chemokine production and CD4+ T cell recruitment were found in the lungs of mice reconstituted with WT eosinophils. This suggested that although eosinophil production of IL-13 is required for T cell recruitment to the lungs, it is not sufficient for the perpetuation of an allergic asthma response. These data indicate that eosinophils and T cells have an interdependent relationship in the development of allergic asthma. Targeting T cells and eosinophils simultaneously in allergic asthma is an immense challenge. Using small molecule inhibitors against a common protein component in the T cell and eosinophil signaling cascade would be a good way to counteract the effects of these cells during the course of an allergic response. ITK is a non-receptor tyrosine kinase that is expressed in eosinophils and T cells. It is known that this kinase is important in the development of Th2 T cells and that T cells lacking ITK are unable to generate an allergic response. We hypothesized that ITK would also be integral to the function of eosinophils in allergic asthma development. We found that compared to ΔdblGATA reconstituted with WT eosinophils, eosinophils lacking ITK were unable to induce AHR, T cell recruitment to the lung, and TH2 cytokine production when transferred to ΔdblGATA mice and challenged with ovalbumin (OVA). This may partially be due to reduced MAPK signaling in these cells downstream of the CCR3 receptor, as stimulation with Eotaxin-1 led to lower and delayed ERK1/2 activation in these cells. These data suggest that developing drugs against ITK could be one potential therapy to combat allergic asthma.