This proposal targets endothelial cell (EC) biology in leukocyte trafficking and inflammation, focusing on the role of vascular adhesion receptors and activating factors in the control of lymphocyte homing. We have shown that vascular signaling through Galphai protein-linked receptors triggers integrin-dependent lymphocyte arrest in high endothelial venules in lymph nodes and Peyer's patches. The hypothesis is that vascular triggering of lymphocyte integrins is mediated by the emerging family of chemoattractant cytokines, and that these chemokines help control lymphocyte-EC recognition and hence lymphocyte recruitment in a site, inflammatory state, and lymphocyte subset-selective fashion. 1) The ability of novel chemokines to induce rapid ICAM-dependent adhesion of blood-borne naive and memory lymphocyte subsets, and to trigger their arrest under physiologic shear will be explored. Responding lymphocyte subsets will be identified by patterns of differentiation antigen, cytokine, and especially homing receptor expression. 2) The investigator will explore the hypothesis that chemokines can differentially activate lymphocyte beta2 vs. alpha4 integrins, thus providing a novel level of vascular control of leukocyte adhesion and recruitment. 3) The involvement of proadhesive chemokines in EC-triggered lymphocyte adhesion and arrest will be assessed in physiologic models. Antibodies to target chemokines will be used a) to assess in immunohistologic studies their display by vascular endothelium, and hence their availability for participation in physiologic adhesion-triggering responses; and b) to explore their physiologic importance in in vivo homing and in situ videomicroscopic studies of lymphocyte-EC interactions. He will focus initially on hypothesized involvement of high endothelial venule-associated 6Ckine and/or MIP3beta in lymphocyte homing to secondary lymphoid tissues in vivo. 4) Receptor(s) for chemokines implicated in vascular arrest of lymphocytes will be identified, and antibodies against them will be used to characterize their involvement in endothelial interactions and lymphocyte homing into lymphoid tissues and/or sites of inflammation. Finally, in a continuation of earlier Aims, he will 5) evaluate the phenotype of MAdCAM-1-deficient mice. The proposed studies should expand our understanding of the critical role of the vascular endothelium in regulating lymphocyte trafficking during normal and pathologic immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM037734-15
Application #
6342815
Study Section
Pathology A Study Section (PTHA)
Program Officer
Somers, Scott D
Project Start
1987-01-01
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
15
Fiscal Year
2001
Total Cost
$284,719
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Salazar, Nicole; Carlson, Jeffrey C; Huang, Kexin et al. (2018) A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models. Mol Ther 26:1354-1365
Zabel, Brian A; Rott, Alena; Butcher, Eugene C (2015) Leukocyte chemoattractant receptors in human disease pathogenesis. Annu Rev Pathol 10:51-81
Lee, Mike; Kiefel, Helena; LaJevic, Melissa D et al. (2014) Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nat Immunol 15:982-95
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
Hadeiba, Husein; Sato, Tohru; Habtezion, Aida et al. (2008) CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 9:1253-60
Morteau, Olivier; Gerard, Craig; Lu, Bao et al. (2008) An indispensable role for the chemokine receptor CCR10 in IgA antibody-secreting cell accumulation. J Immunol 181:6309-15
Sigmundsdottir, Hekla; Butcher, Eugene C (2008) Environmental cues, dendritic cells and the programming of tissue-selective lymphocyte trafficking. Nat Immunol 9:981-7
Zabel, Brian A; Nakae, Susumu; Zuniga, Luis et al. (2008) Mast cell-expressed orphan receptor CCRL2 binds chemerin and is required for optimal induction of IgE-mediated passive cutaneous anaphylaxis. J Exp Med 205:2207-20
Allen, Samantha J; Zabel, Brian A; Kirkpatrick, John et al. (2007) NMR assignment of human chemerin, a novel chemoattractant. Biomol NMR Assign 1:171-3

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