Our goal is to define the role(s) of a novel chemotactic factor and its receptor in leukocyte homing and biology. Extensive preliminary data lead us to hypothesize that this chemoattractant/receptor pair has a significant role in the trafficking of subsets of dendritic cells, key antigen processing and presenting cells that initiate and regulate immune responses in vivo. The factor has been expressed, purified and shown to attract in vitro differentiated and circulating blood dendritic cell subsets. It circulates in plasma in a proform whose activity is dramatically enhanced by proteolytic events triggered by coagulation; activation can be mediated by the serine protease plasmin, linking the tissue fibrinolytic cascade with a mechanism for dendritic cell recruitment. Additional proteases that can mediate cleavage, and the cleavage site(s) associated with chemotactic activation will be identified. Cell type and tissue expression and regulation of the attractant gene and protein will be determined as well, using quantitative RT-PCR and in situ hybridization to characterize mRNA levels, and generating monoclonal antibodies for immunohistochemistry. Structure/function studies will probe the role of key structural elements. Anti-receptor Mabs and chimeric ligand-Ig have been generated and will be used to study the regulation of cell surface receptors during in vitro differentiation and maturation of monocyte or bone marrow-derived DC; and by dendritic cell and other leukocyte subsets in vivo by flow cytometry. Receptor expression assessed by MAb staining will be correlated with chemotactic responses to the ligand. Finally, the role of this novel chemoattractant/receptor combination in dendritic cell development, trafficking and function will be determined in studies employing inhibitory antibodies to the attractant, and receptor deficient, gene -targeted mice. The effects of these interventions on dendritic cell recruitment, positioning and phenotype in normal and inflamed tissues; on induction and kinetics of immune responses; and on immune pathology in selected models of inflammation, will be determined. The proposed studies promise to define an important regulator of immune responses, and may suggest novel strategies to enhance immunity for vaccination, or to suppress immunity for transplantation, autoimmune and allergic diseases.
| Graham, Kareem L; Zhang, Jian V; Lewén, Susanna et al. (2014) A novel CMKLR1 small molecule antagonist suppresses CNS autoimmune inflammatory disease. PLoS One 9:e112925 |
| Kulig, Paulina; Kantyka, Tomasz; Zabel, Brian A et al. (2011) Regulation of chemerin chemoattractant and antibacterial activity by human cysteine cathepsins. J Immunol 187:1403-10 |
| Huss, Ryan S; Huddleston, James I; Goodman, Stuart B et al. (2010) Synovial tissue-infiltrating natural killer cells in osteoarthritis and periprosthetic inflammation. Arthritis Rheum 62:3799-805 |
| Graham, Kareem L; Zabel, Brian A; Loghavi, Sanam et al. (2009) Chemokine-like receptor-1 expression by central nervous system-infiltrating leukocytes and involvement in a model of autoimmune demyelinating disease. J Immunol 183:6717-23 |
| Skrzeczy?ska-Moncznik, Joanna; Stefa?ska, Anna; Zabel, Brian A et al. (2009) Chemerin and the recruitment of NK cells to diseased skin. Acta Biochim Pol 56:355-60 |
