Short-term homing assay reveals a critical role for lymphocyte function-associated antigen-1 in the hepatic recruitment of lymphocytes in graft-versus-host disease
ABSTRACT The liver is a major target organ of graft versus host disease (GvHD) with massive infiltration of alloreactive lymphocytes resulting in hepatitis and hepatocyte injury. Although adhesive mechanisms have been implicated in the biology of GvHD hepatitis, the identity of homing receptors involved in the initial recruitment of cells from the blood is not known.
We have developed a short-term homing assay in a model of murine GvHD. Splenocytes from donors at an active stage of GvHD were injected intravenously into adoptive recipients also undergoing GvHD. The recruitment of cells to the liver was assessed 6h after cell transfer.
Activated donor CD8 and CD4 lymphocytes expressed lymphocyte function antigen-1 (LFA-1), alpha4-integrins, and P-selectin binding ligands, and localized more efficiently than naïve T cells. Immunoneutralization of LFA-1 reduced the recruitment of CD8 and CD4 lymphocytes to the liver by more than 60%. Anti-LFA-1 antibody also markedly reduced infiltration of lymphocytes in periportal areas and protected against hepatocellular damage.
We demonstrate a critical role of LFA-1 in the recruitment of activated lymphocytes to the liver and in immune-cell mediated hepatitis. LFA-1 may be an effective therapeutic target for protecting the liver following bone marrow transplantation.
SourceAvailable from: Thorsten PetersBiology of Blood and Marrow Transplantation 02/2008; 14(2). DOI:10.1016/j.bbmt.2007.12.392 · 3.35 Impact Factor
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ABSTRACT: CD8 T cells play a critical role in several pathological conditions affecting the liver, most notably viral hepatitis. Accordingly, understanding the mechanisms that modulate the intrahepatic recruitment of CD8 T cells is of paramount importance. Some of the rules governing the behavior of these cells in the liver have been characterized at the population level, or have been inferred by studying the intrahepatic behavior of other leukocyte subpopulations. In contrast to most microvascular beds where leukocyte adhesion is restricted to the endothelium of post-capillary venules, it is now becoming clear that in the liver leukocytes, including CD8 T cells, can efficiently interact with the endothelium of hepatic capillaries (i.e. the sinusoids). While physical trapping has been proposed to play an important role in leukocyte adhesion to hepatic sinusoids, there is mounting evidence that T cell recruitment to the liver is highly regulated and depends on recruitment signals that are either constitutive or induced by inflammation. We review here several specific adhesive mechanisms that have been shown to regulate CD8 T cell trafficking within the liver, as well as highlight recent data that establish platelets as key cellular regulators of intrahepatic CD8 T cell accumulation.Molecular Immunology 11/2012; DOI:10.1016/j.molimm.2012.10.032 · 3.00 Impact Factor