PD-1 immune checkpoint blockade promotes brain leukocyte infiltration and diminishes cyst burden in a mouse model of Toxoplasma infection

Research output: Contribution to journalArticle

Abstract

Tissue cysts, the hallmark of chronic Toxoplasma gondii infection, are predominantly located in the brain making clearance of the parasite difficult. Currently available anti-T. gondii drugs are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. We examined whether abrogation of inhibitory signaling pathways that maintain T cells in an exhausted state can be exploited for treating T. gondii tissue cysts. By using a mouse model of chronic toxoplasmosis, we showed immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway results in a significant reduction in brain cyst number (77% lower). We showed leukocyte infiltration (CD3+ T cells, CD8+ T cells, and CD11b + cells) in the leptomeninges, choroid plexus, and subependymal tissue, which are known routes of entry of immune cells into the brain, and in proximal brain parenchyma. Our study provides proof of concept for blockade of immune checkpoint inhibitors as a therapy for chronic toxoplasmosis and potentially for other brain pathogens.

Original languageEnglish (US)
Pages (from-to)55-62
Number of pages8
JournalJournal of Neuroimmunology
Volume319
DOIs
StatePublished - Jun 15 2018

Fingerprint

Toxoplasma
Toxoplasmosis
Cysts
Leukocytes
Brain
Infection
T-Lymphocytes
Choroid Plexus
Parasites
Pharmaceutical Preparations

Keywords

  • Brain leukocyte infiltration
  • Chronic toxoplasmosis
  • CNS pathogen
  • CSF-filled compartments
  • Cyst burden
  • MAG1 antibody
  • PD-1/PD-L1 pathway
  • Treatment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

Cite this

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title = "PD-1 immune checkpoint blockade promotes brain leukocyte infiltration and diminishes cyst burden in a mouse model of Toxoplasma infection",
abstract = "Tissue cysts, the hallmark of chronic Toxoplasma gondii infection, are predominantly located in the brain making clearance of the parasite difficult. Currently available anti-T. gondii drugs are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. We examined whether abrogation of inhibitory signaling pathways that maintain T cells in an exhausted state can be exploited for treating T. gondii tissue cysts. By using a mouse model of chronic toxoplasmosis, we showed immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway results in a significant reduction in brain cyst number (77{\%} lower). We showed leukocyte infiltration (CD3+ T cells, CD8+ T cells, and CD11b + cells) in the leptomeninges, choroid plexus, and subependymal tissue, which are known routes of entry of immune cells into the brain, and in proximal brain parenchyma. Our study provides proof of concept for blockade of immune checkpoint inhibitors as a therapy for chronic toxoplasmosis and potentially for other brain pathogens.",
keywords = "Brain leukocyte infiltration, Chronic toxoplasmosis, CNS pathogen, CSF-filled compartments, Cyst burden, MAG1 antibody, PD-1/PD-L1 pathway, Treatment",
author = "Jian-Chun Xiao and Ye Li and Yolken, {Robert H} and Viscidi, {Raphael P}",
year = "2018",
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AU - Xiao, Jian-Chun

AU - Li, Ye

AU - Yolken, Robert H

AU - Viscidi, Raphael P

PY - 2018/6/15

Y1 - 2018/6/15

N2 - Tissue cysts, the hallmark of chronic Toxoplasma gondii infection, are predominantly located in the brain making clearance of the parasite difficult. Currently available anti-T. gondii drugs are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. We examined whether abrogation of inhibitory signaling pathways that maintain T cells in an exhausted state can be exploited for treating T. gondii tissue cysts. By using a mouse model of chronic toxoplasmosis, we showed immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway results in a significant reduction in brain cyst number (77% lower). We showed leukocyte infiltration (CD3+ T cells, CD8+ T cells, and CD11b + cells) in the leptomeninges, choroid plexus, and subependymal tissue, which are known routes of entry of immune cells into the brain, and in proximal brain parenchyma. Our study provides proof of concept for blockade of immune checkpoint inhibitors as a therapy for chronic toxoplasmosis and potentially for other brain pathogens.

AB - Tissue cysts, the hallmark of chronic Toxoplasma gondii infection, are predominantly located in the brain making clearance of the parasite difficult. Currently available anti-T. gondii drugs are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. We examined whether abrogation of inhibitory signaling pathways that maintain T cells in an exhausted state can be exploited for treating T. gondii tissue cysts. By using a mouse model of chronic toxoplasmosis, we showed immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway results in a significant reduction in brain cyst number (77% lower). We showed leukocyte infiltration (CD3+ T cells, CD8+ T cells, and CD11b + cells) in the leptomeninges, choroid plexus, and subependymal tissue, which are known routes of entry of immune cells into the brain, and in proximal brain parenchyma. Our study provides proof of concept for blockade of immune checkpoint inhibitors as a therapy for chronic toxoplasmosis and potentially for other brain pathogens.

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KW - Chronic toxoplasmosis

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KW - Treatment

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