Mucosal epithelial chemokine (CCL28) in asthma

Stanford University, Stanford CA

Investigators

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Abstract

(Applicant's Abstract) Recent studies suggest that a newly identified subfamily of chemoattractant cytokines (chemokines) contributes to the recruitment of memory and effector lymphocytes responsible for tissue-selective regional immune responses 1-3. These chemokines can be expressed by epithelial cells either constitutively, or in an inflammation-inducible fashion, and are hypothesized to control the recruitment, retention and/or function of lymphocytes specialized for mucosal (e.g. intestinal or bronchial) vs. cutaneous immune responses. We have identified a new member of this subfamily, mucosal epithelial chemokine (MEC), that is expressed in bronchial epithelium3. Furthermore we have recently found that MEC (designated CCL28) can bind to two different chemokine receptors, CCR3 and CCR10. One or both of these receptor are expressed by lymphocytes, eosinophils and mast cells, inflammatory cells implicated in the pathogenesis of asthma. We hypothesize that MEC significantly influences the initiation and progression of mucosal inflammation in asthma, by regulating the recruitment and retention of leukocyte populations in healthy and inflamed airways. To test this hypothesis we will first carry out a comprehensive study of the cellular sites and patterns of MEC expression in normal and inflamed airways, and we will define the mechanisms of MEC regulation in airway epithelium. We will next determine the ability of MEC to induce chemotaxis of leukocyte populations implicated in the pathogenesis of asthma, focussing on memory and effector lymphocyte populations. In the final aim we will utilize inhibitory anti-MEC antibodies and MEC deficient mice to determine the contribution of MEC to the development of allergic airway disease in our mouse "asthma" models. These studies have the potential to define a novel element in the control of pulmonary leukocyte trafficking and the pathophysiology of asthma.