Genetic models to study chemokine biology in the lung

Leukocyte migration from the blood to peripheral tissue is important for the clearance of infectious pathogens, but it is also a major component of autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. An improved understanding of the molecular events underlying leukocyte migration in vivo would aid in the design of novel strategies to intervene therapeutically in these and other diseases. In recent years, much interest has focused on the possibility of using antagonists of chemokine function to block leukocyte migration in vivo. This interest has stemmed from two basic observations. First, chemokines have been long-known to induce directed migration of leukocytes in vivo. Second, many chemokine genes are highly expressed at sites of inflammation. To directly test the hypothesis that this expression is of functional importance to leukocyte migration in vivo, some investigators have conducted chemokine gain-of-function and loss-of-function experiments using genetically modified mice (1). In this chapter, we summanze recent genetic experiments, from our laboratories, that have revealed important roles for chemokme function in vivo, with a particular emphasis on chemokme function in the lung We will review our work on the CXC chemokines KC and lungkine, as well as our work on the chemokme receptors CCR6 and CCR8.