Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
Stanley Division of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
J Neuroimmunol. 2018 Jun 15;319:55-62. doi: 10.1016/j.jneuroim.2018.03.013. Epub 2018 Mar 30.
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.
组织囊肿是慢性弓形虫感染的标志，主要位于大脑中，使寄生虫难以清除。目前可用的抗弓形虫药物对囊肿无效，也不能预防潜伏性弓形体病的复发。我们研究了是否可以利用消除抑制性信号通路来阻止 T 细胞进入衰竭状态，从而治疗弓形虫组织囊肿。通过使用慢性弓形虫病的小鼠模型，我们发现针对程序性死亡-1（PD-1）途径的免疫检查点阻断导致脑中囊数量显著减少（减少 77%）。我们观察到脑膜、脉络丛和室管膜下组织中的白细胞浸润（CD3+T 细胞、CD8+T 细胞和 CD11b+细胞），这些部位是免疫细胞进入大脑的已知途径，以及在大脑近皮质组织中。我们的研究为免疫检查点抑制剂阻断作为慢性弓形体病治疗方法提供了概念验证，并且可能适用于其他脑部病原体。
