High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4+ T cell arrest on the inflamed BBB under flow in vitro

Journal of Neuroinflammation

Research

Susan Goelz¹  Fabien Gosselet²  James L. McGrath³  Dale Glavin³  Alexander Bär⁴  Britta Engelhardt⁴  Mykhailo Vladymyrov⁴  Sasha Soldati⁴  Hideaki Nishihara⁵ 

[1] Biogen, Cambridge, MA, USA;Blood-Brain Barrier Laboratory, University of Artois, Lens, France;Department of Biomedical Engineering, University of Rochester, Rochester, NY, USA;Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland;Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland;Department of Neurotherapeutics, Yamaguchi University, Yamaguchi, Japan;

关键词: Blood–brain barrier;    Brain microvascular endothelial cells;    Central nervous system;    Extended interval dosing;    Intercellular adhesion molecule-1;    Multiple sclerosis;    Natalizumab;    Progressive multifocal leukoencephalopathy;    Standard interval dosing;    Vascular cell-adhesion molecule-1;   

DOI  :  10.1186/s12974-023-02797-8

 received in 2023-03-10, accepted in 2023-05-02,  发布年份 2023

来源: Springer

【 摘 要 】

IntroductionThe humanized anti-α4 integrin blocking antibody natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS) that is associated with the risk of progressive multifocal leukoencephalopathy (PML). While extended interval dosing (EID) of NTZ reduces the risk for PML, the minimal dose of NTZ required to maintain its therapeutic efficacy remains unknown.ObjectiveHere we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector/memory CD4+ T cell subsets or of PBMCs to the blood–brain barrier (BBB) under physiological flow in vitro.ResultsMaking use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of α4-integrins failed to abrogate T cell arrest to the inflamed BBB under physiological flow. Complete inhibition of shear resistant T cell arrest required additional inhibition of β2-integrins, which correlated with a strong upregulation of endothelial intercellular adhesion molecule (ICAM)-1 on the respective BBB models investigated. Indeed, NTZ mediated inhibition of shear resistant T cell arrest to combinations of immobilized recombinant vascular cell adhesion molecule (VCAM)-1 and ICAM-1 was abrogated in the presence of tenfold higher molar concentrations of ICAM-1 over VCAM-1. Also, monovalent NTZ was less potent than bivalent NTZ in inhibiting T cell arrest to VCAM-1 under physiological flow. In accordance with our previous observations ICAM-1 but not VCAM-1 mediated T cell crawling against the direction of flow.ConclusionTaken together, our in vitro observations show that high levels of endothelial ICAM-1 abrogate NTZ mediated inhibition of T cell interaction with the BBB. EID of NTZ in MS patients may thus require consideration of the inflammatory status of the BBB as high levels of ICAM-1 may provide an alternative molecular cue allowing for pathogenic T cell entry into the CNS in the presence of NTZ.

【 授权许可】

CC BY   
© The Author(s) 2023

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