Neutrophils are capable of recognizing linear polymers of glucose linked in ß-1,3 conformation (viz., ß-glucan) which is a cell wall component of infectious microorganisms including yeast, fungi and bacteria. The recognition of ß-glucan by these cells is of benefit to host defense in two ways: first, since glucose does not occur in mature mammalian glycoproteins, ß-glucan provides a recognition mechanism through which neutrophils can bind and clear microorganisms without the need for opsonization; and second, ß-glucan binding stimulates neutrophil functions including chemotaxis, phagocytosis and oxidative burst. However, the mechanism(s) by which these inflammatory cells recognize ß-glucan is not defined. Work in this laboratory suggests that human neutrophils detect ß-glucan through novel interactions with cell surface integrins producing subsequent effects on cell motility. Ongoing efforts are directed at defining the mechanism(s) of this recognition and the second messenger signaling events that are triggered within the migrating cell. This work entails microscopic techniques in cell migration and immunocytochemistry, as well as protein biochemistry and molecular biology to investigate intracellular signaling pathways.
Translational Research: Although the innate immune system has been studied for a number of years, a well-defined pharmacological intervention to beneficially prime the function of neutrophils or macrophages is still lacking. This is so because the favorable aspects of cell priming needed to improve host defense is often accompanied by the overproduction of proinflammatory mediators at levels that cannot be tolerated by human subjects. PGG-ß-glucan, a soluble form of ß-glucan extracted from Saccharomyces cerevsiae, has been shown to prime leukocyte functions while not eliciting cytokine production in experimental animals and in high-risk surgical patients. It is this desirable property of PGG-ß-glucan that allowed for its evaluation in clinical trials where it was well tolerated by patients participating in phase III studies at the doses used in this report and underlies its therapeutic potential as an immunomodulator. Therapeutic opportunities in improving host response to cancer and infectious disease are being pursued by Biothera Pharmaceuticals.