TY - JOUR
T1 - ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions
AU - Willrodt, Ann-Helen
AU - Salabarria, Ann-Charlott
AU - Schineis, Philipp
AU - Ignatova, Desislava
AU - Hunter, Morgan Campbell
AU - Vranova, Martina
AU - Golding-Ochsenbein, Alexandra M
AU - Sigmund, Elena
AU - Romagna, Annatina
AU - Strassberger, Verena
AU - Fabbi, Marina
AU - Ferrini, Silvano
AU - Cursiefen, Claus
AU - Neri, Dario
AU - Guenova, Emmanuella
AU - Bock, Felix
AU - Halin, Cornelia
PY - 2019
Y1 - 2019
N2 - Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell adhesion molecule of the immunoglobulin superfamily and has been implicated in diverse pathophysiological processes including T cell activation, leukocyte trafficking, and (lymph)angiogenesis. However, exploring the therapeutic potential of ALCAM blockade in immune-mediated inflammatory disorders has been difficult due to the lack of antibodies with blocking activity toward murine ALCAM. In this study, we identified and characterized a monoclonal antibody with high affinity and specificity for murine ALCAM. This antibody reduced in vitro T cell activation induced by antigen-presenting dendritic cells (DCs) as well as (trans)migration of murine DCs across lymphatic endothelial monolayers. Moreover, it reduced emigration of DCs from in vitro-cultured human skin biopsies. Similarly, antibody-based blockade of ALCAM reduced (lymph)angiogenic processes in vitro and decreased developmental lymphangiogenesis in vivo to levels observed in ALCAM-deficient mice. Since corneal allograft rejection is an important medical condition that also involves (lymph)angiogenesis, DC migration and T cell activation, we investigated the therapeutic potential of ALCAM blockade in murine corneal disease. Blocking ALCAM lead to DC retention in corneas and effectively prevented corneal allograft rejection. Considering that we also detected ALCAM expression in human corneal DCs and lymphatics, our findings identify ALCAM as a potential novel therapeutic target in human corneal allograft rejection.
AB - Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell adhesion molecule of the immunoglobulin superfamily and has been implicated in diverse pathophysiological processes including T cell activation, leukocyte trafficking, and (lymph)angiogenesis. However, exploring the therapeutic potential of ALCAM blockade in immune-mediated inflammatory disorders has been difficult due to the lack of antibodies with blocking activity toward murine ALCAM. In this study, we identified and characterized a monoclonal antibody with high affinity and specificity for murine ALCAM. This antibody reduced in vitro T cell activation induced by antigen-presenting dendritic cells (DCs) as well as (trans)migration of murine DCs across lymphatic endothelial monolayers. Moreover, it reduced emigration of DCs from in vitro-cultured human skin biopsies. Similarly, antibody-based blockade of ALCAM reduced (lymph)angiogenic processes in vitro and decreased developmental lymphangiogenesis in vivo to levels observed in ALCAM-deficient mice. Since corneal allograft rejection is an important medical condition that also involves (lymph)angiogenesis, DC migration and T cell activation, we investigated the therapeutic potential of ALCAM blockade in murine corneal disease. Blocking ALCAM lead to DC retention in corneas and effectively prevented corneal allograft rejection. Considering that we also detected ALCAM expression in human corneal DCs and lymphatics, our findings identify ALCAM as a potential novel therapeutic target in human corneal allograft rejection.
KW - Allografts
KW - Animals
KW - Antigens, CD/genetics
KW - Biopsy
KW - Cell Adhesion Molecules, Neuronal/antagonists & inhibitors
KW - Cell Movement/genetics
KW - Corneal Transplantation
KW - Dendritic Cells/immunology
KW - Fetal Proteins/antagonists & inhibitors
KW - Genetic Engineering
KW - Graft Rejection/genetics
KW - Immunity
KW - Lymphangiogenesis
KW - Lymphatic Vessels
KW - Lymphocyte Activation/genetics
KW - Mice
KW - Mice, Knockout
KW - Skin/immunology
KW - T-Lymphocytes/immunology
UR - https://www.scopus.com/pages/publications/85065414731
U2 - 10.3389/fimmu.2019.00759
DO - 10.3389/fimmu.2019.00759
M3 - Article
C2 - 31031759
SN - 1664-3224
VL - 10
SP - 759
JO - Frontiers in Immunology
JF - Frontiers in Immunology
ER -