Conditional Transgenic Models to Study Chemokine Biology

Leukocyte migration is a crucial component of defense against many infections and in the pathogenesis of multiple inflammatory disorders. Therefore, the elucidation of the mechanisms responsible for leukocyte recruitment is critical for the development of novel therapeutic approaches for these conditions. Among the molecules implicated in regulating leukocyte trafficking are the chemokines, low-molecular-weight secreted molecules that interact with G-protein-coupled receptors. Evidence supporting an important role for chemokines in leukocyte migration derives from studies employing (1) in vitro chemotaxis assays (1 –4 ), (2) in vivo chemotaxis assays involving administration of exogenous recombinant mediators into a body cavity (5 ), (3) animal models of disease (6 –10 ), and (4) transgenic models (11 ). Although critical to our understanding of these processes, both in vitro and in vivo chemotaxis assays are limited because they do not fully reproduce the complex environment of healthy or diseased tissues. On the other hand, the myriad perturbations in the biochemical and physical microenvironment of diseased tissue, including the expression of multiple mediators, changes in the characteristics of resident cells, and the influx of inflammatory cells, make it difficult to discern the role of a single mediator. In this context, studies on genetically engineered mice are uniquely positioned to examine the biology of both ligands and receptors in the environment of the relevant tissue without the confounding influence of coexisting disease.