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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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Objective<\/jats:title>\n                <jats:p>Here we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector\/memory CD4<jats:sup>+<\/jats:sup> T cell subsets or of PBMCs to the blood\u2013brain barrier (BBB) under physiological flow in vitro<jats:italic>.<\/jats:italic><\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Making use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of \u03b14-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 \u03b22-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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>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.\n<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12974-023-02797-8","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T09:03:02Z","timestamp":1684832582000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4+ T cell arrest on the inflamed BBB under flow in vitro"],"prefix":"10.1186","volume":"20","author":[{"given":"Sasha","family":"Soldati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"B\u00e4r","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mykhailo","family":"Vladymyrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Glavin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James L.","family":"McGrath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Gosselet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Nishihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Goelz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britta","family":"Engelhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,23]]},"reference":[{"issue":"10130","key":"2797_CR1","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1016\/S0140-6736(18)30481-1","volume":"391","author":"AJ Thompson","year":"2018","unstructured":"Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. 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