High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4+ T cell arrest on the inflamed BBB under flow in vitro
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 reduc...
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02797-8 |
| _version_ | 1797817861320736768 |
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| author | Sasha Soldati Alexander Bär Mykhailo Vladymyrov Dale Glavin James L. McGrath Fabien Gosselet Hideaki Nishihara Susan Goelz Britta Engelhardt |
| author_facet | Sasha Soldati Alexander Bär Mykhailo Vladymyrov Dale Glavin James L. McGrath Fabien Gosselet Hideaki Nishihara Susan Goelz Britta Engelhardt |
| author_sort | Sasha Soldati |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T08:59:42Z |
| format | Article |
| id | doaj.art-ac48d8c3d465490f8a3c4c2f105b86bd |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-13T08:59:42Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-ac48d8c3d465490f8a3c4c2f105b86bd2023-05-28T11:23:22ZengBMCJournal of Neuroinflammation1742-20942023-05-0120112210.1186/s12974-023-02797-8High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4+ T cell arrest on the inflamed BBB under flow in vitroSasha Soldati0Alexander Bär1Mykhailo Vladymyrov2Dale Glavin3James L. McGrath4Fabien Gosselet5Hideaki Nishihara6Susan Goelz7Britta Engelhardt8Theodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernTheodor Kocher Institute, University of BernDepartment of Biomedical Engineering, University of RochesterDepartment of Biomedical Engineering, University of RochesterBlood-Brain Barrier Laboratory, University of ArtoisTheodor Kocher Institute, University of BernBiogenTheodor Kocher Institute, University of BernAbstract 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.https://doi.org/10.1186/s12974-023-02797-8Blood–brain barrierBrain microvascular endothelial cellsCentral nervous systemExtended interval dosingIntercellular adhesion molecule-1Multiple sclerosis |
| spellingShingle | Sasha Soldati Alexander Bär Mykhailo Vladymyrov Dale Glavin James L. McGrath Fabien Gosselet Hideaki Nishihara Susan Goelz Britta Engelhardt 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 Blood–brain barrier Brain microvascular endothelial cells Central nervous system Extended interval dosing Intercellular adhesion molecule-1 Multiple sclerosis |
| 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 | Blood–brain barrier Brain microvascular endothelial cells Central nervous system Extended interval dosing Intercellular adhesion molecule-1 Multiple sclerosis |
| url | https://doi.org/10.1186/s12974-023-02797-8 |
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