Brain capillary obstruction during neurotoxicity in a mouse model of anti-CD19 chimeric antigen receptor T-cell therapy.
CD19 chimeric antigen receptor
capillary
neurotoxicity
neurovascular unit
two-photon imaging
Journal
Brain communications
ISSN: 2632-1297
Titre abrégé: Brain Commun
Pays: England
ID NLM: 101755125
Informations de publication
Date de publication:
2022
2022
Historique:
received:
05
07
2021
revised:
19
10
2021
accepted:
30
12
2021
entrez:
16
2
2022
pubmed:
17
2
2022
medline:
17
2
2022
Statut:
epublish
Résumé
Immunotherapy for haematologic malignancies with CD19-directed chimeric antigen receptor T cells has been highly successful at eradicating cancer but is associated with acute neurotoxicity in ∼40% of patients. This neurotoxicity correlates with systemic cytokine release syndrome, endothelial activation and disruption of endothelial integrity, but it remains unclear how these mechanisms interact and how they lead to neurologic dysfunction. We hypothesized that dysfunction of the neurovascular unit is a key step in the development of neurotoxicity. To recapitulate the interaction of the intact immune system with the blood-brain barrier, we first developed an immunocompetent mouse model of chimeric antigen receptor T-cell treatment-associated neurotoxicity. We treated wild-type mice with cyclophosphamide lymphodepletion followed by escalating doses of murine CD19-directed chimeric antigen receptor T cells. Within 3-5 days after chimeric antigen receptor T-cell infusion, these mice developed systemic cytokine release and abnormal behaviour as measured by daily neurologic screening exams and open-field testing. Histologic examination revealed widespread brain haemorrhages, diffuse extravascular immunoglobulin deposition, loss of capillary pericyte coverage and increased prevalence of string capillaries. To measure any associated changes in cerebral microvascular blood flow, we performed
Identifiants
pubmed: 35169706
doi: 10.1093/braincomms/fcab309
pii: fcab309
pmc: PMC8833245
doi:
Types de publication
Journal Article
Langues
eng
Pagination
fcab309Subventions
Organisme : NINDS NIH HHS
ID : K08 NS118138
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097775
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG063031
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.
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