Selectins, selectin ligands, integrins, and immunoglobulin-like adhesion molecules are critically involved in leukocyte-endothelial adhesion in inflammation, leukocyte-platelet interactions, and lymphocyte trafficking. Emigration of neutrophils and lymphocytes is preceded by rolling, which is largely mediated by selectins alpha4beta7 integrin and L-selectin are necessary to direct lymphocyte homing to Peyer's patches and other gut- associated lymphatic tissues. P- and E-selectins are rapidly up-regulated on the endothelial surface upon exposure to inflammatory stimuli and are involved in neutrophil and monocyte recruitment and homing on T helper 1 (Th1)-like lymphocytes. Beta2 integrins (CD18) are expressed on the leukocyte surface and are involved in leukocyte adhesion molecules in leukocyte recruitment and tissue damage in a spontaneous mouse model of Crohn's disease (CD), the SAMP1/Yit mouse. We hypothesize that (1) these mice express adhesion molecules relevant to the trafficking of T lymphocytes, neutrophils, and other leukocytes; (2) leukocyte and/or endothelial adhesion molecules are required for development of inflammatory disease in immunodeficient mice adaptively transferred with CD4+ T cells from SAMP1/Yit mice; and (3) CD4+ T lymphocytes use specific adhesion molecules to home to the terminal ileum of mice and cause disease in this model. Methods include the use of transgenic and knockout mice, intravital microscopy, tissue histology, immunohistochemistry, flow cytometry, measurement of soluble adhesion molecules, and lymphocyte homing assays. Adoptive transfer of SAMP1/Yit CD4+ T cells will be used to produce CD-like disease in immunodeficient (RAG-2 -/-) mice and in adhesion molecule-deficient mice back-crossed into the RAG-2 -/- mutation. Project 4 is aimed to identifying the molecular mechanisms of lymphocyte homing and inflammatory cell recruitment to CD lesions in vivo. Insights into the mechanisms of T lymphocyte homing and inflammatory cell recruitment will provide a rationale for clinical studies investigating the efficacy of interventions aimed at modulating the expression and/or function of leukocyte-endothelial adhesion molecules.
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