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

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

Author(s): 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;
Details: Publication Year 2023-07,Volume 10,Issue #4,Page e200117
Journal Title: Neurology: Neuroimmunology & Neuroinflammation
Publication Type: Research article
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.
Publisher: Wolters Kluwer
Keywords: Mice; Animals; Perforin; Neuroinflammatory Diseases; *Malaria, Cerebral; Endothelial Cells; *Susac Syndrome; Mice, Knockout; CD8-Positive T-Lymphocytes; Disease Models, Animal
Department(s): Laboratory Research
PubMed ID: 37080596
Publisher's Version: https://doi.org/10.1212/NXI.0000000000200117
Open Access at Publisher's Site: https://doi.org/10.1212/nxi.0000000000200117
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-09-14 03:09:14

Last Modified: 2023-09-14 03:09:44