The attraction of leukocytes to sites of inflammation and infection is an essential component of the host response to disease. This process is controlled by chemokines, which are chemotactic cytokines. IP-10 (CXCL 10) is a chemokine that specifically attracts effector T cells and """"""""innate lymphocytes"""""""" by activating a seven transmembrane spanning G protein-coupled chemokine receptor, CXCR3, which is expressed on these cells. Chemokines also have activities on non-hematopoietic cells and may be important mediators that link inflammation to tissue repair processes. In this regard, IP-10 inhibits angiogenesis and fibrosis in vivo. The molecular mechanism of these later effects have not been clearly established. IP-10, like many other chemokines, is a basic protein that binds to proteoglycans and also has the ability to form higher order aggregates. The functional consequences of these interactions are not clear, although they likely play important roles in IP-10's biological activity in vivo, especially in cells such as endothelial cells and fibroblasts where CXCR3 expression has been difficult to demonstrate. In this renewal application, we propose to continue our studies on IP-10 to define the structural domains that mediate its biological activities in vivo, to determine the mechanisms that control the differential regulation and function of the three CXCR3 ligands -- IP-10, MIG and I-TAC -- in vivo, and to define the role of CXCR3 and its ligands in the trafficking of defined subsets of antigen-specific CD4 and CD8 cells in vivo. Specifically, we propose: (1) To determine the structural domains of IP-10 that mediate its binding to CXCR3 and proteoglycans and its tendency to oligomerize, and the biological consequences each of these interactions have for IP-10's ability to induce T cell recruitment and inhibit angiogenesis and fibrosis in vivo; (2) To determine the unique roles of IP-10 and MIG in allograft rejection in a model of lung transplantation, and to determine the cellular and molecular mechanisms regulating the differential expression of these two CXCR3 ligands in this model; (3) To determine the role of IP-10, MIG, I-TAC and CXCR3 in the generation and trafficking of defined subsets of antigen-specific of CD4 and CD8 T cells in vivo. Studies supported by this grant have contributed to our understanding of IP- 10 and have helped establish IP- 10 and CXCR3 as attractive candidates for modulating the immune response in clinically relevant diseases, such as solid organ transplantation, pulmonary fibrosis and cancer. The current proposal will extend and refine our knowledge of this important clinically relevant chemokine-chemokine receptor system.
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