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Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Mediated Neuroinflammation
Carmen Gonzalez-Fierro1, Coralie Fonte1, Eloïse Dufourd1
1From the Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) (C.G.-F., C.F., E.D., V.C., G.M.-B., R.S.L., C.B.), University of Toulouse, CNRS, INSERM, UPS, France; Theodor Kocher Institute (S.A., B.E.), University of Bern, Switzerland; Laboratory of Immunology (R.R.C., B.X.), National Eye Institute, National Institutes of Health, Bethesda, MD; Department of Infectious and Tropical Diseases (G.M.-B.), Toulouse University Hospital, France; Auckland Cancer Society Research Centre (J.A.S.), Faculty of Medical and Health Sciences, The University of Auckland, New Zealand; Cancer Immunology Program (J.A.T.), Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology (J.A.T.), The University of Melbourne, Parkville, Australia; Department of Neuroimmunology (J.B.), Center for Brain Research, Medical University of Vienna, Austria; and Department of Immunology (R.S.L., C.B.), Toulouse University Hospital, France.
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.
