Cell cooperation in development of eosinophil-predominant inflammation in airways

A large body of research supports a pathogenic role of Th2 cells in allergic diseases such as asthma. These disorders are characterized by recruitment to selected peripheral tissues of a mixed leukocyte inflammatory infiltrate including a predominant eosinophil component. The development of this inflammatory response is dependenton accumulation of Th2 cells in the affected tissues. Our studies aim to define the mechanisms that control the development of this tissue inflammatory response, focusing particularly on the mechanisms that recruit Th2 cells to the lung and airway. We have found that Th2 cells are on their own poorly competent for antigen-induced recruitment to the lung. By contrast, Th1 cells are avidly recruited to the lungs in response to airway antigen challenge. More important, recruitment of Th1 cells to the lung resulted in enhanced recruitment of Th2 cells to this tissue. The increased Th1 cell-induced recruitment of Th2 cells was associated with upregulation of endothelial vascular cell adhesion molecule-1 (VCAM-1) expression in airway-associated endothelial cells and could be largely blocked by systemic treatment with a monoclonal anti-VCAM-1 antibody. Systemic blocking of tumor necrosis factor (TNF) also blunted the airway inflammatory response. The prominent roles of TNF and VCAM-1 in recruitment of Th2 cells suggested that an inflammatory microenvironment was essential for the recruitment of Th2 cells. In fact, recruitment of Th2 cells to the airway could be induced in an antigen-independent fashion by proinflammatory stimuli such as intranasal instillation of endotoxin. This antigen nonspecificity of the Th2 cell recruitment suggested a model in which Th2 cell recruitment is in response to general inflammatory signals rather than to antigen itself. This model provides an explanation for the clinical observation that bacterial or viral respiratory tract infections are associated with disease exacerbations in allergic asthmatics. More generally, these data imply that Th2 cells, like other leukocytes, are recruited efficiently to sites of tissue inflammation, and that these nonspecifically recruited Th2 cells have substantial potential to modulate local inflammatory processes.