Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell–Mediated Neuroinflammation - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Neurology Neuroimmunology & Neuroinflammation Année : 2023

Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell–Mediated Neuroinflammation

Résumé

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.

Dates et versions

hal-04186063 , version 1 (23-08-2023)

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Carmen Gonzalez-Fierro, Coralie Fonte, Eloïse Dufourd, Vincent Cazaentre, Sidar Aydin, et al.. Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell–Mediated Neuroinflammation. Neurology Neuroimmunology & Neuroinflammation, 2023, 10 (4), pp.e200117. ⟨10.1212/NXI.0000000000200117⟩. ⟨hal-04186063⟩
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