Chemosensory motility behavior of phagocytic white blood cells is recognized as a key component of the host inflammatory response to tissue insult and invasion. Polymorphonuclear leukocytes and macrophages exhibit chemotaxis and chemokinesis in response to chemical mediators present in inflammatory sites, and abnormalities in either the cellular responses or the chemical mediators have been found in many individuals showing increased susceptibility to and severity of infectious, inflammatory, and malignant diseases. In order to improve diagnosis and treatment of such conditions, medical scientists are searching for a reliable way to relate in vitro assays for phagocyte chemosensory motility behavior to in vivo performance of the inflammatory response. This proposal describes an engineering approach toward achievement of this goal, combining experiments with mathematical modeling. A phenomenological mathematical model for cell population movement will be tested using data obtained from in vitro cell migration assays, including the under-agarose assay (both linear and cylindrical geometries), the filter assay, and the collagen gel assay. We will attempt to determine values of the model parameters for leukocyte and macrophage chemotaxis and chemokinesis in the presence of known attractants. Although these are phenomenological parameters, they are defined in terms of fundamental cell behavioral properties: speed, persistence time, and directional orientation. We will test whether there does in fact exist a theoretically-predicted relationship between these fundamental cell properties and the phenomenological parameters. Then, changes in these fundamental cell properties, whether caused by physical or chemical modulators or due to intrinsic abnormalities, should be reflected quantitatively by the values of the phenomenological parameters. We will examine this possibility by investigating the changes found in the parameter values caused by drugs such as colchicine and levamisole, and the differences found among macrophage subpopulations. These parameters might then be useful for predicting population behavior in an inflammatory response. We will investigate this by using them to interpret quantitative cell kinetic data from an in vivo experimental system: the gingival crevice leukocyte accumulation assay. We will attempt to discover whether these parameters can be used to correlate in vitro cell behavior with in vivo cell kinetics.
