Gonzalez-Fierro, Carmen; Fonte, Coralie; Dufourd, Eloïse; Cazaentre, Vincent; Aydin, Sidar; Engelhardt, Britta; Caspi, Rachel R; Xu, Biying; Martin-Blondel, Guillaume; Spicer, Julie A; Trapani, Joseph A; Bauer, Jan; Liblau, Roland S; Bost, Chloé (2023). Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Mediated Neuroinflammation. Neurology: Neuroimmunology and Neuroinflammation, 10(4) Wolters Kluwer Health 10.1212/NXI.0000000000200117
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BACKGROUND AND OBJECTIVES
Alteration 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.
METHODS
In 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.
RESULTS
Using an in vitro coculture system, we first identified perforin as an essential molecule for killing of BBB-ECs by CD8 T cells. We then found that short-term pharmacologic inhibition of perforin commencing after disease onset restored motor function and inhibited the neuropathology. Perforin inhibition resulted in preserved BBB-EC viability, maintenance of the BBB, and reduced CD8 T-cell accumulation in the brain and retina.
DISCUSSION
Therefore, perforin-dependent cytotoxicity plays a key role in the death of BBB-ECs inflicted by autoreactive CD8 T cells in a preclinical model and potentially represents a therapeutic target for CD8 T cell-mediated neuroinflammatory diseases, such as cerebral malaria and Susac syndrome.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute |
UniBE Contributor: |
Aydin, Sidar, Engelhardt, Britta |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2332-7812 |
Publisher: |
Wolters Kluwer Health |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
21 Apr 2023 11:23 |
Last Modified: |
22 Apr 2023 15:21 |
Publisher DOI: |
10.1212/NXI.0000000000200117 |
PubMed ID: |
37080596 |
BORIS DOI: |
10.48350/181891 |
URI: |
https://boris.unibe.ch/id/eprint/181891 |
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