TY - JOUR
T1 - PD-1 immune checkpoint blockade promotes brain leukocyte infiltration and diminishes cyst burden in a mouse model of Toxoplasma infection
AU - Xiao, Jianchun
AU - Li, Ye
AU - Yolken, Robert H.
AU - Viscidi, Raphael P.
N1 - Funding Information:
This work was supported by the Stanley Medical Research Institute .
Publisher Copyright:
© 2018 Elsevier B.V.
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.
KW - Brain leukocyte infiltration
KW - CNS pathogen
KW - CSF-filled compartments
KW - Chronic toxoplasmosis
KW - Cyst burden
KW - MAG1 antibody
KW - PD-1/PD-L1 pathway
KW - Treatment
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U2 - 10.1016/j.jneuroim.2018.03.013
DO - 10.1016/j.jneuroim.2018.03.013
M3 - Article
C2 - 29685290
AN - SCOPUS:85044941292
SN - 0165-5728
VL - 319
SP - 55
EP - 62
JO - Journal of Neuroimmunology
JF - Journal of Neuroimmunology
ER -