Ranran Han1, Jiaying Luo1, Yanchao Shi1, Yang Yao1, Junwei Hao2. 1. From the Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China. 2. From the Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, China. hjw@tmu.edu.cn.
Abstract
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a neurologically destructive stroke, for which no valid treatment is available. This preclinical study examined the therapeutic effect of PD-L1 (programmed death ligand 1), a B7 family member and a ligand for both PD-1 (programmed death 1) and B7-1 (CD80), in a murine ICH model. METHODS: ICH was induced by injecting autologous blood into 252 male C57BL/6 and Rag1-/- mice. One hour later, ICH mice were randomly assigned to receive an intraperitoneal injection of vehicle, PD-L1, or anti-PD-L1 antibody. Neurological function was assessed along with brain edema, brain infiltration of immune cells, blood-brain barrier integrity, neuron death, and mTOR (mammalian target of rapamycin) pathway products. RESULTS: PD-L1 significantly attenuated neurological deficits, reduced brain edema, and decreased hemorrhage volume in ICH mice. PD-L1 specifically downsized the number of brain-infiltrating CD4+ T cells and the percentages of Th1 and Th17 cells but increased the percentages of Th2 and regulatory T cells. In the PD-L1-treated group, we observed an amelioration of the inflammatory milieu, decreased cell death, and enhanced blood-brain barrier integrity. PD-L1 also inhibited the mTOR pathway. The administration of anti-PD-L1 antibody produced the opposite effects to those of PD-L1 in ICH mice. CONCLUSIONS: PD-L1 provided protection from the damaging consequences of ICH.
BACKGROUND AND PURPOSE:Intracerebral hemorrhage (ICH) is a neurologically destructive stroke, for which no valid treatment is available. This preclinical study examined the therapeutic effect of PD-L1 (programmed death ligand 1), a B7 family member and a ligand for both PD-1 (programmed death 1) and B7-1 (CD80), in a murineICH model. METHODS:ICH was induced by injecting autologous blood into 252 male C57BL/6 and Rag1-/- mice. One hour later, ICHmice were randomly assigned to receive an intraperitoneal injection of vehicle, PD-L1, or anti-PD-L1 antibody. Neurological function was assessed along with brain edema, brain infiltration of immune cells, blood-brain barrier integrity, neuron death, and mTOR (mammalian target of rapamycin) pathway products. RESULTS:PD-L1 significantly attenuated neurological deficits, reduced brain edema, and decreased hemorrhage volume in ICHmice. PD-L1 specifically downsized the number of brain-infiltrating CD4+ T cells and the percentages of Th1 and Th17 cells but increased the percentages of Th2 and regulatory T cells. In the PD-L1-treated group, we observed an amelioration of the inflammatory milieu, decreased cell death, and enhanced blood-brain barrier integrity. PD-L1 also inhibited the mTOR pathway. The administration of anti-PD-L1 antibody produced the opposite effects to those of PD-L1 in ICHmice. CONCLUSIONS:PD-L1 provided protection from the damaging consequences of ICH.