Shetty, Shishir (2011)
Ph.D. thesis, University of Birmingham.
Lymphocyte infiltration of the liver drives the progression of all inflammatory liver diseases. Lymphocyte homing to the liver occurs within the hepatic sinusoids. The hepatic sinusoidal endothelial cells (HSEC) that line these channels have a unique phenotype and lack conventional adhesion molecules, making these cells a potential organ specific target for therapy. I carried out a detailed analysis of the expression of CLEVER-1 in the human liver and show that it is expressed on sinusoidal endothelium in situ and in vitro and at other sites of lymphocyte recruitment in the inflamed liver including neovessels, portal associated lymphoid tissue and vessels supplying hepatocellular carcinomas. The expression of CLEVER-1 on HSEC in vitro was upregulated by hepatocyte growth factor. Flow based adhesion assays with HSEC demonstrated that CLEVER-1 mediated lymphocyte transmigration and that this activity was subset specific with preferential activity for B cells and T regulatory (Treg) cells. Using confocal imaging I was able to show that CLEVER-1 mediates Treg migration via the transcellular route through HSEC. This is the first report of transcellular migration in the liver.
This study identifies CLEVER-1 as a novel lymphocyte recruitment signal to the liver and a potential target for therapy in chronic liver diseases.
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