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In an immunocompetent mouse model, we show by in vivo two-photon imaging that CD19-CAR T treatment causes brain capillary plugging by circulating CAR-T cells and other CD45+ leukocytes, as well as cortical hypoxia. This is accompanied by increased endothelial ICAM-1 and VCAM-1 expression in the brain capillary-venule transition zone, where most of the capillary stalls occur. In the mouse model, circulating CAR-T cells strongly upregulate integrin \u03b14\u03b21 affinity to VCAM-1, but not affinity of integrin \u03b1L\u03b22 to ICAM-1. Blockade of integrin \u03b14 but not integrin \u03b1L improves locomotion behavior. In vitro, human brain microendothelial cells upregulate ICAM-1 more than VCAM-1 in response to TNF, IFN-\u03b3, and IL-1\u03b2. In a 3D brain human microvessel model, treatment with TNF and IFN-\u03b3 is sufficient to induce adhesion of CAR T cells under flow conditions, which is blocked synergistically by antibodies against integrins \u03b14 and \u03b1L. Finally, patients with the highest levels of TNF and IFN-\u03b3 also have the highest blood levels of soluble ICAM-1 and VCAM-1, which in turn correlate with ICANS. Integrin \u03b14 but not \u03b1L increases in CAR-T cells after they are infused into patients. Combined data from patients, mouse models and in vitro microvessels indicate differential regulation of interactions of ICAM-1 and VCAM-1 with their respective leukocyte integrins. Overall, our study supports the hypothesis that cytokine-driven upregulation of endothelial-leukocyte adhesion is sufficient to induce acute, reversible neurotoxicity.<\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>During CAR T cell therapy, cytokine release induces white blood cell stalling in brain capillaries by upregulating ICAM-1\/VCAM-1-integrin interactions.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.19.638920","type":"posted-content","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T23:30:22Z","timestamp":1740526222000},"source":"Crossref","is-referenced-by-count":4,"title":["Cytokines mediate increased endothelial-leukocyte interaction and brain capillary plugging during CAR T cell neurotoxicity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4705-9755","authenticated-orcid":false,"given":"Lina","family":"Park","sequence":"first","affiliation":[{"name":"Norcliffe Foundation Center for Integrative Brain Research, Seattle Children\u2019s Research Institute; 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