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
Department of Medicine, Stanford University, Palo Alto, California, United States Journal of Hepatology
(Impact Factor: 11.34).
07/2006; 44(6):1132-40. DOI: 10.1016/j.jhep.2005.11.042
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.
Available from: Matteo Iannacone
- "Antigen non-specific adhesion of activated CD8 T cells to LSEC has been proposed to occur via VCAM-1/␣ 4 -integrin (John and Crispe, 2004). In a graft versus host disease model, however, ␣ 4 -integrin was found to be dispensable for the recruitment of activated CD8+ T cells into the liver (Sato et al., 2006). Also, naïve CD8 T cells appear not to need ␣ 4 -integrin to be recruited to the uninflamed liver (Bertolino et al., 2005). "
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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; 55(1). DOI:10.1016/j.molimm.2012.10.032 · 2.97 Impact Factor
Available from: Henrik Thorlacius
- "Thus, these data suggest for the first time that LFA-1 is a key regulator of pancreatic injury in AP. This adds AP to the list of conditions in which LFA-1 has turned out to be a significant target; these include septic and cholestatic liver injury (Li et al., 2004; Dold et al., 2008), alcoholic liver disease (Ohki et al., 1998), viral hepatitis (Matsumoto et al., 2002), endotoxaemia (Li et al., 2004), graft-versus-host disease (Kimura et al., 1996; Sato et al., 2006) and colonic ischaemiareperfusion (Wan et al., 2003). In this context, it should be mentioned that a previous study reported that depletion of neutrophils increases pancreatic haemorrhage in response to taurocholate challenge (Ryschich et al., 2009), suggesting that leucocytes protect against haemorrhage in AP. "
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ABSTRACT: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP.
Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1.
Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillary venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas.
Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas.
British Journal of Pharmacology 05/2011; 163(2):413-23. DOI:10.1111/j.1476-5381.2011.01225.x · 4.84 Impact Factor
Available from: Karin scharffetter-kochanek
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