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.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Sato
Tohru
T
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, and the Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. tsato@stanford.edu
Habtezion
Aida
A
Beilhack
Andreas
A
Schulz
Stephan
S
Butcher
Eugene
E
Thorlacius
Henrik
H
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001681:Biological Assay; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors / Q000502:physiology
D000906:Antibodies; D016169:Lymphocyte Function-Associated Antigen-1; D016201:Receptors, Lymphocyte Homing