The purpose of the project is to investigate the biological roles of members of the chemokine family of cytokines by studying the actions of chemokines and their receptors in vivo, particularly in mouse models of infectious disease, inflammation and cancer. Chemokines and their receptors are critical for leukocyte trafficking. Our experiments will provide important information for understanding in which therapeutic contexts in humans manipulating the chemokine system might be beneficial. This laboratory discovered two mouse chemokines, Crg-2/CXCL10 and Mig/CXCL9 that are highly induced by gamma interferon and that share a receptor, CXCR3. We discovered human - and cloned the mouse analogue of - CCR6, the receptor for the chemokine MIP-3alpha/CCL20 and reportedly for the beta-defensin anti-microbial peptides. We discovered the HIV-1 co-receptor/chemokine receptor STRL33/CXCR6. We also cloned and characterized the human CCR9A and CCR9B, receptors for the chemokine TECK/CCL25. Part of this project uses gene-targeted mice that we have made (CXCL9 and CCR6 knockout mice) as well as other gene-targeted mice that we have obtained from other investigators to study the roles of these ligand/receptor groups in models of immunity and inflammation in mice. In addition, we have produced polyclonal and monoclonal neutralizing antibodies to block the actions of mouse chemokines in vivo. Collaborative work in the last year has revealed critical roles for the chemokine receptor CXCR3 in mobilization of natural killer cells, whcih are important for responses agianst pathogens and tumors, as well as in transplant rejection. These results may provide new insights into mechanisms of host defense and suggest pathways of immune-mediated inflammation that can be augmented or inhibited for therapeutic benefit.
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