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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069212-13
Application #
7323267
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Howcroft, Thomas K
Project Start
1996-03-01
Project End
2008-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
13
Fiscal Year
2008
Total Cost
$398,381
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Murray, Henry W; Luster, Andrew D; Zheng, Hua et al. (2017) Gamma Interferon-Regulated Chemokines in Leishmania donovani Infection in the Liver. Infect Immun 85:
Lian, Jeffrey; Luster, Andrew D (2015) Chemokine-guided cell positioning in the lymph node orchestrates the generation of adaptive immune responses. Curr Opin Cell Biol 36:1-6
Mikucki, M E; Fisher, D T; Matsuzaki, J et al. (2015) Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun 6:7458
Chow, Melvyn T; Luster, Andrew D (2014) Chemokines in cancer. Cancer Immunol Res 2:1125-31
Rocha, Viviane Zorzanelli; Folco, Eduardo J; Ozdemir, Cafer et al. (2014) CXCR3 controls T-cell accumulation in fat inflammation. Arterioscler Thromb Vasc Biol 34:1374-81
Woodruff, Matthew C; Heesters, Balthasar A; Herndon, Caroline N et al. (2014) Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine. J Exp Med 211:1611-21
Baptista, A P; Olivier, B J; Goverse, G et al. (2013) Colonic patch and colonic SILT development are independent and differentially regulated events. Mucosal Immunol 6:511-21
Arvikar, Sheila L; Collier, Deborah S; Fisher, Mark C et al. (2013) Clinical correlations with Porphyromonas gingivalis antibody responses in patients with early rheumatoid arthritis. Arthritis Res Ther 15:R109
Wu, Qiang; Gardiner, Gail J; Berry, Elizabeth et al. (2013) ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection. PLoS One 8:e72955
Bromley, Shannon K; Yan, Sha; Tomura, Michio et al. (2013) Recirculating memory T cells are a unique subset of CD4+ T cells with a distinct phenotype and migratory pattern. J Immunol 190:970-6

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