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|Title:||The role of basophils in the late asthmatic response and the effect of alarmin cytokines on basophil pro-inflammatory activity|
|Department:||Medical Sciences (Division of Physiology/Pharmacology)|
|Abstract:||There is emerging evidence that the alarmin cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-25 (IL-25), and IL-33 are critical mediators of T helper cell type-2 (Th2)-driven inflammation in allergic airway disease. Although there is a myriad of data pertaining to the interaction between these alarmins and immune cells, there is still very little known on how alarmin cytokines can influence the activity of basophils in allergic asthma. The overall objectives of this thesis were to examine the involvement of basophils in the late asthmatic response (LAR) of allergic asthma and to determine whether their pro-inflammatory activity is influenced by alarmin cytokines. Initially, we investigated the change in activity and migration of basophils following allergen inhalation in mild allergic asthmatics. We showed that a subset of activated basophils migrate from the bone marrow into peripheral blood and then to the airways during an airway allergen challenge (Chapters 2-5). We found expression of surface activation markers and intracellular Type 2 cytokines was increased after an allergen challenge for up to 24 hours (Chapter 3). Next, we examined the change in expression on basophils of receptors for TSLP, IL-25, and IL-33 following an allergen challenge (Chapters 3 and 4). We reported that basophil surface receptor expression for alarmin cytokines was markedly increased post-allergen challenge within the peripheral blood and airway samples. In addition, we investigated the effect of these alarmin cytokines on basophil activity in vitro, demonstrating that they can directly stimulate basophil activation and Type 2 cytokine intracellular expression, as well as prime eotaxin-induced migration (Chapters 3 and 4). Finally, to explore the pro-inflammatory response of basophils to the airway microenvironment, we examined the effect of airway samples collected post-allergen on basophils in vitro (Chapter 4). We showed that basophil activation and Type 2 cytokine intracellular expression were up-regulated following incubation with 7 hour post-allergen airway samples, and could be inhibited following treatment with a monoclonal antibody (mAb) to the common β-chain (βc) for IL-3/IL-5/granulocyte-macrophage colony-stimulating factor (GM-CSF). The novel work presented herein augments the available evidence that basophils play a role in the LAR of allergic asthma that may be in part mediated by interaction with alarmin cytokines. These observations support the notion that the basophil/alarmin cytokine axis is a potentially important therapeutic target for allergic asthma. Continued investigation is required to determine if blockade of this axis can inhibit or attenuate allergic airway inflammation and bronchoconstriction.|
|Appears in Collections:||Open Access Dissertations and Theses|
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|Aug 5 Post-defence thesis revisions_GG10AUG2015.docx||Main Article||10.85 MB||Microsoft Word XML||View/Open|
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