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

Content Provider	Springer Nature : BioMed Central
Author	Soldati, Sasha Bär, Alexander Vladymyrov, Mykhailo Glavin, Dale McGrath, James L. Gosselet, Fabien Nishihara, Hideaki Goelz, Susan Engelhardt, Britta
Abstract	Introduction The 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. Objective Here 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. Results Making 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. Conclusion Taken 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.
Related Links	https://jneuroinflammation.biomedcentral.com/counter/pdf/10.1186/s12974-023-02797-8.pdf
Ending Page	22
Page Count	22
Starting Page	1
File Format	HTM / HTML
ISSN	17422094
DOI	10.1186/s12974-023-02797-8
Journal	Journal of Neuroinflammation
Issue Number	1
Volume Number	20
Language	English
Publisher	BioMed Central
Publisher Date	2023-05-23
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Neurobiology Immunology 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
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology Cellular and Molecular Neuroscience Neurology
Journal Impact Factor	9.3/2023
5-Year Journal Impact Factor	9.8/2023

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