title: Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS.
abstract: The ability to selectively block the entry of leukocytes into the central nervous system (CNS) without compromising the immune system is an attractive therapeutic approach for treating multiple sclerosis (MS). Using endothelial CD146-deficienct mice as a MS model, we found that endothelial CD146 plays an active role in the CNS-directed extravasation of encephalitogenic T cells, including CD146(+) TH1 and TH17 lymphocytes. Moreover, treating both active and passive MS models with the anti-CD146 antibody AA98 significantly decreased the infiltrated lymphocytes in the CNS and decreased neuroinflammation. Interestingly, the ability of AA98 to inhibit the migration of CD146(+) lymphocytes was dependent on targeting endothelial CD146, but not lymphocytic CD146. These results suggest a key molecular target located on the blood-brain barrier endothelium that mediates the extravasation of inflammatory cells into the CNS. In addition, our data suggest that the AA98 is a promising candidate for treating MS and other CNS autoimmune diseases.
authors.affiliation: Key Laboratory of Protein and Peptide Pharmaceuticals, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Duan
authors.forename: Shu
authors.initials: S
authors.lastname: Xing
authors.forename: Yongting
authors.initials: Y
authors.lastname: Luo
authors.forename: Liqun
authors.initials: L
authors.lastname: Feng
authors.forename: Irene
authors.initials: I
authors.lastname: Gramaglia
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Di
authors.initials: D
authors.lastname: Lu
authors.forename: Qiqun
authors.initials: Q
authors.lastname: Zeng
authors.forename: Kelong
authors.initials: K
authors.lastname: Fan
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.forename: Dongling
authors.initials: D
authors.lastname: Yang
authors.forename: Zhihai
authors.initials: Z
authors.lastname: Qin
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.forename: Xiyun
authors.initials: X
authors.lastname: Yan
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051929:CD146 Antigen / Q000276:immunology; D004660:Encephalitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology
chemical_list: D051929:CD146 Antigen; C497903:Mcam protein, mouse