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

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.

Source: Neurology Neuroimmunology and Neuroinflammation - April 20, 2023 Category: Neurology Authors: Gonzalez-Fierro, C., Fonte, C., Dufourd, E., Cazaentre, V., Aydin, S., Engelhardt, B., Caspi, R. R., Xu, B., Martin-Blondel, G., Spicer, J. A., Trapani, J. A., Bauer, J., Liblau, R. S., Bost, C. Tags: Autoimmune diseases Research Article Source Type: research