Gonzalez-Fierro, CarmenCarmenGonzalez-FierroFonte, CoralieCoralieFonteDufourd, EloïseEloïseDufourdCazaentre, VincentVincentCazaentreAydin, SidarSidarAydinEngelhardt, BrittaBrittaEngelhardt0000-0003-3059-9846Caspi, Rachel RRachel RCaspiXu, BiyingBiyingXuMartin-Blondel, GuillaumeGuillaumeMartin-BlondelSpicer, Julie AJulie ASpicerTrapani, Joseph AJoseph ATrapaniBauer, JanJanBauerLiblau, Roland SRoland SLiblauBost, ChloéChloéBost2024-10-252024-10-252023-07https://boris-portal.unibe.ch/handle/20.500.12422/166602BACKGROUND 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.en600 - Technology::610 - Medicine & healtharticle10.48350/1818913708059610.1212/NXI.0000000000200117