A Herpes Simplex Virus-Derived Replicative Vector Expressing LIF Limits Experimental Demyelinating Disease and Modulates Autoimmunity
A Herpes Simplex Virus-Derived Replicative Vector Expressing LIF Limits Experimental Demyelinating Disease and Modulates Autoimmunity
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DOI：
10.1371/journal.pone.0064200
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发表时间：
2013-05-20
期刊：
影响因子：
3.7
通讯作者：
Hukkanen, Veijo
中科院分区：
文献类型：
--
作者：
Nygardas, Michaela;Paavilainen, Henrik;Hukkanen, Veijo
单纯疱疹病毒1型（HSV-1）具有可用于开发基因治疗载体的特性。HSV的嗜神经性使得能够将治疗基因递送至神经系统。我们使用细菌人工染色体（BAC）构建了一个基于HSV-1（17（+））的复制载体，缺失神经毒力基因gamma（1）34.5，并表达白血病抑制因子（LIF）作为治疗实验性自身免疫性脑脊髓炎（EAE）的转基因。EAE是中枢神经系统（CNS）的可诱导T细胞介导的自身免疫性疾病，并且用作多发性硬化症的动物模型。脱髓鞘和炎症是这两种疾病的标志。LIF是一种细胞因子，具有限制CNS自身免疫性疾病中的脱髓鞘和少突胶质细胞损失以及影响T细胞介导的自身免疫应答的潜力。在这项研究中，SJL/J小鼠，诱导EAE，治疗与HSV-LIF载体颅内和随后的变化，在急性疾病的疾病参数和免疫反应进行了研究。在急性感染期间，在CNS中检测到复制的HSV-LIF及其DNA，并且载体扩散到脊髓，但无毒力。与未处理的小鼠相比，HSV-LIF显著改善了EAE，并导致脑中少突胶质细胞数量增加。HSV-LIF疗法还在急性疾病期间诱导CNS中免疫调节细胞因子和T细胞群体标志物表达的有利变化。这些数据表明，BAC衍生的HSV载体适用于CNS疾病的基因治疗，并可用于测试免疫调节因子治疗EAE的治疗潜力。
Herpes simplex virus type 1 (HSV-1) has properties that can be exploited for the development of gene therapy vectors. The neurotropism of HSV enables delivery of therapeutic genes to the nervous system. Using a bacterial artificial chromosome (BAC), we constructed an HSV-1(17(+))-based replicative vector deleted of the neurovirulence gene gamma(1)34.5, and expressing leukemia inhibitory factor (LIF) as a transgene for treatment of experimental autoimmune encephalomyelitis (EAE). EAE is an inducible T-cell mediated autoimmune disease of the central nervous system (CNS) and is used as an animal model for multiple sclerosis. Demyelination and inflammation are hallmarks of both diseases. LIF is a cytokine that has the potential to limit demyelination and oligodendrocyte loss in CNS autoimmune diseases and to affect the T-cell mediated autoimmune response. In this study SJL/J mice, induced for EAE, were treated with a HSV-LIF vector intracranially and the subsequent changes in disease parameters and immune responses during the acute disease were investigated. Replicating HSV-LIF and its DNA were detected in the CNS during the acute infection, and the vector spread to the spinal cord but was non-virulent. The HSV-LIF significantly ameliorated the EAE and contributed to a higher number of oligodendrocytes in the brains when compared to untreated mice. The HSV-LIF therapy also induced favorable changes in the expression of immunoregulatory cytokines and T-cell population markers in the CNS during the acute disease. These data suggest that BAC-derived HSV vectors are suitable for gene therapy of CNS disease and can be used to test the therapeutic potential of immunomodulatory factors for treatment of EAE.