Journal article
Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Mediated Neuroinflammation
C Gonzalez-Fierro, C Fonte, E Dufourd, V Cazaentre, S Aydin, B Engelhardt, RR Caspi, B Xu, G Martin-Blondel, JA Spicer, JA Trapani, J Bauer, RS Liblau, C Bost
Neurology Neuroimmunology and Neuroinflammation | LIPPINCOTT WILLIAMS & WILKINS | Published : 2023
Open access
Abstract
Background and ObjectivesAlteration of the blood-brain barrier (BBB) at the interface between blood and CNS parenchyma is prominent in most neuroinflammatory diseases. In several neurologic diseases, including cerebral malaria and Susac syndrome, a CD8 T cell-mediated targeting of endothelial cells of the BBB (BBB-ECs) has been implicated in pathogenesis.MethodsIn this study, we used an experimental mouse model to evaluate the ability of a small-molecule perforin inhibitor to prevent neuroinflammation resulting from cytotoxic CD8 T cell-mediated damage of BBB-ECs.ResultsUsing an in vitro coculture system, we first identified perforin as an essential molecule for killing of BBB-ECs by CD8 T c..
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Awarded by Institut National de la Santé et de la Recherche Médicale
Funding Acknowledgements
This work was supported by grants from Agence Nationale pour la Recherche CE17-0014 (RSL), Fondation pour la Recherche Medicale (Prix Line Pomaret Delalande [CGF]; DEQ20170336727 [RSL]) ARSEP-French MS society: ARSEP 2019-20 (RSL), BETPSY RHU 18- RHUS-0012(RSL), Austrian Science Fund FWF: P34864-B (JB). The early stages of perforin inhibitor drug development were funded by the Strategic Drug Discovery Initiative (SDDI) Program of the Wellcome Trust UK (JAT).