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Dernière publication 07/07/2023

Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Me

Background and objectives: Alteration of the blood-brain barrier (BBB) at the interface between blood and CNS parenchyma is prominent in most...

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    [title] => Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Me
    [paragraph] => Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Mediated Neuroinflammation
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Authors
Gonzalez-Fierro C, Fonte C, Dufourd E, Cazaentre V, Aydin S, Engelhardt B, Caspi RR, Xu B, Martin-Blondel G, Spicer JA, Trapani JA, Bauer J, Liblau RS, Bost C.

 Lab
Toulouse University Hospital, France
Journal
Neurol Neuroimmunol Neuroinflamm
Abstract
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. 

Keywords/Topics
Fonctions cérébrales; Fonctions cérébrales; Adiposité
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