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High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro
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 r...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204262/ https://www.ncbi.nlm.nih.gov/pubmed/37221552 http://dx.doi.org/10.1186/s12974-023-02797-8 |
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author | Soldati, Sasha Bär, Alexander Vladymyrov, Mykhailo Glavin, Dale McGrath, James L. Gosselet, Fabien Nishihara, Hideaki Goelz, Susan Engelhardt, Britta |
author_facet | Soldati, Sasha Bär, Alexander Vladymyrov, Mykhailo Glavin, Dale McGrath, James L. Gosselet, Fabien Nishihara, Hideaki Goelz, Susan Engelhardt, Britta |
author_sort | Soldati, Sasha |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02797-8. |
format | Online Article Text |
id | pubmed-10204262 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-102042622023-05-24 High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro Soldati, Sasha Bär, Alexander Vladymyrov, Mykhailo Glavin, Dale McGrath, James L. Gosselet, Fabien Nishihara, Hideaki Goelz, Susan Engelhardt, Britta J Neuroinflammation Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02797-8. BioMed Central 2023-05-23 /pmc/articles/PMC10204262/ /pubmed/37221552 http://dx.doi.org/10.1186/s12974-023-02797-8 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Soldati, Sasha Bär, Alexander Vladymyrov, Mykhailo Glavin, Dale McGrath, James L. Gosselet, Fabien Nishihara, Hideaki Goelz, Susan Engelhardt, Britta High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro |
title | High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro |
title_full | High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro |
title_fullStr | High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro |
title_full_unstemmed | High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro |
title_short | High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4(+) T cell arrest on the inflamed BBB under flow in vitro |
title_sort | high levels of endothelial icam-1 prohibit natalizumab mediated abrogation of cd4(+) t cell arrest on the inflamed bbb under flow in vitro |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10204262/ https://www.ncbi.nlm.nih.gov/pubmed/37221552 http://dx.doi.org/10.1186/s12974-023-02797-8 |
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