title: Direct evidence for activated CD8+ T cell transmigration across portal vein endothelial cells in liver graft rejection.
abstract: BACKGROUND
  Lymphocyte recruitment into the portal tract is crucial not only for homeostatic immune surveillance but also for many liver diseases. However, the exact route of entry for lymphocytes into portal tract is still obscure. We investigated this question using a rat hepatic allograft rejection model.
  
  
  METHODS
  A migration route was analyzed by immunohistological methods including a recently developed scanning electron microscopy method. Transmigration-associated molecules such as selectins, integrins, and chemokines and their receptors expressed by hepatic vessels and recruited T-cells were analyzed by immunohistochemistry and flow cytometry.
  
  
  RESULTS
  The immunoelectron microscopic analysis clearly showed CD8β(+) cells passing through the portal vein (PV) endothelia. Furthermore, the migrating pathway seemed to pass through the endothelial cell body. Local vascular cell adhesion molecule-1 (VCAM-1) expression was induced in PV endothelial cells from day 2 after liver transplantation. Although intercellular adhesion molecule-1 (ICAM-1) expression was also upregulated, it was restricted to sinusoidal endothelia. Recipient T-cells in the graft perfusate were CD25(+)CD44(+)ICAM-1(+)CXCR3(+)CCR5(-) and upregulated α4β1 or αLβ2 integrins. Immunohistochemistry showed the expression of CXCL10 in donor MHCII(high) cells in the portal tract as well as endothelial walls of PV.
  
  
  CONCLUSIONS
  We show for the first time direct evidence of T-cell transmigration across PV endothelial cells during hepatic allograft rejection. Interactions between VCAM-1 on endothelia and α4β1 integrin on recipient effector T-cells putatively play critical roles in adhesion and transmigration through endothelia. A chemokine axis of CXCL10 and CXCR3 also may be involved.
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Kariya
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan. ueta@dokkyomed.ac.jp.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ueta
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan.|Department of General Surgery, Dalian Medical University, 1st Affiliated Hospital, Dalian, China.
authors.forename: Xue-Dong
authors.initials: XD
authors.lastname: Xu
authors.affiliation: Department of Microscopic Anatomy and Cell Biology, Asahikawa Medical College, Hokkaido, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koga
authors.affiliation: Department of Anatomy and Developmental Biology, School of Medicine, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ezaki
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: Enqiao
authors.initials: E
authors.lastname: Yu
authors.affiliation: Department of Morphological Science, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kusumi
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kitazawa
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sawanobori
authors.affiliation: Division of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ushiki
authors.affiliation: Department of Pediatrics, Dalhousie University/IWK Health Center, Nova Scotia, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Issekutz
authors.affiliation: Department of Anatomy (Macro), Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Matsuno
mesh_terms: D064591:Allografts / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000502:physiology*; D054357:Chemokine CXCL10 / Q000032:analysis; D004727:Endothelium / Q000737:chemistry / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000032:analysis; D007150:Immunohistochemistry; D039041:Integrin alpha4beta1 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D016031:Liver Transplantation / Q000009:adverse effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D008855:Microscopy, Electron, Scanning; D011169:Portal Vein; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D019713:Receptors, CCR5 / Q000032:analysis; D054367:Receptors, CXCR3 / Q000032:analysis; D057705:Transendothelial and Transepithelial Migration; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; C091326:Cxcl10 protein, rat; C515189:Cxcr3 protein, rat; D018960:Hyaluronan Receptors; D039041:Integrin alpha4beta1; D053645:Interleukin-2 Receptor alpha Subunit; D016169:Lymphocyte Function-Associated Antigen-1; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1
keywords: Portal vein endothelia; T-cell; Transmigration; Vascular cell adhesion molecule-1; α4β1 integrin (VLA-4)