ArticleNeurology(R) neuroimmunology & neuroinflammation2023
Effects of a Small-Molecule Perforin Inhibitor in a Mouse Model of CD8 T Cell-Mediated Neuroinflammation.
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Article in Neurology(R) neuroimmunology & neuroinflammation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12citing papers in PubMed
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Who cites it
12 citing papers in PubMed, 16 citations in OpenAlex.
- Pharmacological inhibition of perforin dampens CD8Diabetologia · 2026Article
- CD11c+ CD8 T cells cause IFN-γ-dependent autoimmune neuroinflammation that is restrained by PD-1 signaling.JCI insight · 2026Article
- Cytotoxic T lymphocytes and their dual role in modulating blood-brain barrier integrity in immune-mediated neurological pathologies.Journal of translational medicine · 2025Review
- Hypoxia and IL-15 Cooperate to Induce Perforin Expression by CD8 T Cells and Promote Damage to the Skin in Murine Cutaneous Leishmaniasis.The Journal of investigative dermatology · 2025Article
- Perceiving traumatic brain injury from glymphatic system.Molecular psychiatry · 2025Review
- CD8 T cells as drivers of blood-brain barrier disruption.Trends in neurosciences · 2025Review
- Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation.Acta neuropathologica communications · 2025Article
- Single-cell sequencing reveals intracranial microvasculature-derived CXCL12 promotes CD8Journal of neuroinflammation · 2025Article
- The Multifaceted Role of L-Type Amino Acid Transporter 1 at the Blood-Brain Barrier: Structural Implications and Therapeutic Potential.Molecular neurobiology · 2025Review
- The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders.Antioxidants (Basel, Switzerland) · 2024Review
- Endothelial cells and macrophages as allies in the healthy and diseased brain.Acta neuropathologica · 2024Review
- Pharmacologic inhibition of dipeptidyl peptidase 1 (cathepsin C) does not blockFrontiers in pharmacology · 2024Article
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Authors and funding
14 authors at 8 institutions in 6 countries.
Carmen Gonzalez-FierroFrom 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.
Coralie FonteFrom 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.
Eloïse DufourdFrom 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.
Vincent CazaentreFrom 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.
Sidar AydinFrom 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.
Britta EngelhardtFrom 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.
Rachel R CaspiFrom 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.
Biying XuFrom 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.
Guillaume Martin-BlondelFrom 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.
Julie A SpicerFrom 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.
Joseph A TrapaniFrom 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.
Jan BauerFrom 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.
Roland S LiblauFrom 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. roland.liblau@inserm.fr.
Chloé BostFrom 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.
University of Bern · CHNational Institutes of Health · USCancer Society of New Zealand · NZMedical University of Vienna · ATNational Eye Institute · USPeter MacCallum Cancer Centre · AUUniversité de Toulouse · FRUniversity of Melbourne · AU
Funding
Genetic, Cellular and Molecular Mechanisms in Autoimmunity to RetinaZIAEY000184 · NEI · NATIONAL EYE INSTITUTE · PI CASPI, RACHEL R. · 2009 to 2025
$51.7MAustrian Science Fund FWF P 34864Wellcome Trust
Abstract
BACKGROUND AND
objectivesAlteration 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.
methodsIn 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.
resultsUsing 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.
Indexed as
Malaria, CerebralSusac SyndromeAnimalsCD8-Positive T-LymphocytesDisease Models, AnimalEndothelial CellsMiceMice, KnockoutNeuroinflammatory DiseasesPerforinPerforin
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