IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis
IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis
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DOI：
10.1038/gt.2008.10
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发表时间：
2008-04-01
期刊：
影响因子：
5.1
通讯作者：
Furlan, R.
中科院分区：
文献类型：
--
作者：
Butti, E.;Bergami, A.;Furlan, R.
中枢神经系统（CNS）递送抗炎细胞因子，例如白介素4（IL4），具有多发性硬化症（MS）治疗的希望。我们先前已经表明，短期疱疹病毒1型1型介导的IL4基因疗法能够抑制MS和非人类灵长类动物中MS动物模型的实验性自身免疫性脑脊髓炎（EAE）。在这里，我们表明，单个表达IL4的辅助辅助腺病毒载体（HD-AD）施用到脑脊液（CSF）循环中，免疫补偿小鼠的循环允许持续转导神经上皮细胞，并长期（长达5个月）CNS CNS经过毒性表达。受到慢性和复发性EAE影响的小鼠一旦注射了表达IL4的HD-AD载体，就会从该疾病中显示出临床和神经生理恢复。治疗效应是由于IL4在发炎的CNS区域，趋化因子（CCL1，CCL17和CCL22）中的能力提高，能够具有抑制剂功能募集调节性T细胞（CD4（+）CD69 CD69 CD25（+）FOXP3（+））。表达抗炎分子的HD-AD载体的CSF传递可能代表了中枢神经系统炎症性疾病的有价值的治疗选择。
Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4(+) CD69 CD25(+) Foxp3(+)) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.