腺相关病毒（AAV）介导mIL-27p28基因治疗小鼠实验性自身免疫性葡萄膜炎（EAU）

发布时间：2018-03-17 09:10

本文选题：白介素-27p28　切入点：基因治疗　出处：《重庆医科大学》2012年硕士论文　论文类型：学位论文

【摘要】：葡萄膜炎是一种多见于青年人的对视功能有损害的炎症性疾病，它是导致视力丧失的重要原因之一。在这个疾病中治疗中，应用最广的是糖皮质激素和其他免疫抑制剂。但是这些药物能引起一系列甚至危及生命的副作用。白细胞介素（IL）-27是最近才被鉴定出来的IL-6/IL-12家族成员。它是由EBI3和IL-27p28两个亚单位组成的异质二聚体，其在抑制Th1和Th17反应中发挥着重要的作用，，且可能由此控制自身免疫性炎症。最近有研究表明系统注射外源IL-27可以明显地抑制实验性自身免疫性脑膜炎（EAE）、实验性自身免疫性葡萄膜炎（EAU）和胶原诱导的关节炎（CIA）的疾病程度。和异二聚体IL-27一样，单纯的IL-27p28也有抑制体外CD4阳性T淋巴细胞产生IL-17的能力，它还可以在一定程度上推迟发病和降低疾病严重程度。在人类和动物各类视网膜疾病模型中的基因治疗取得了显著的成功。眼睛是一个特别适合于基因治疗的器官，另外，单次和低剂量给药以及眼部免疫赦免可以减少免疫原性，眼内注射引起的轻度的宿主免疫反应没有对视网膜产生毒性，也没有抑制转基因的表达。在很多器官腺相关病毒（AAV）介导的临床基因治疗试验都已经通过，但是在EAU模型中仅有很少的研究。在本研究中，我们成功地注射携带有mIL-27p28基因的AAV2载体病毒颗粒到B10RIII小鼠眼内视网膜下，结果表明p28在眼内呈稳定的高浓度表达，且明显抑制EAU炎症程度，还发现这个抑制作用和眼内IL-17表达的下调和眼内IL-10表达的上调是相关的。
[Abstract]:Uveitis is an inflammatory disease that is often seen in young people with impaired visual function. It is one of the major causes of visual loss. The most widely used drugs are glucocorticoids and other immunosuppressants. But these drugs can cause a series of even life-threatening side effects. Interleukin-27 is a recently identified member of the IL-6/IL-12 family. It is composed of EBI3 and. Heterogeneous dimer composed of two subunits of IL-27p28, It plays an important role in inhibiting the reaction of Th1 and Th17. Recent studies have shown that systemic injection of exogenous IL-27 can significantly inhibit experimental autoimmune meningitis, experimental autoimmune uveitis (EAU) and collagen-induced arthritis. The degree of disease is the same as that of heterodimer IL-27. IL-27p28 alone can also inhibit the production of IL-17 by CD4 positive T lymphocytes in vitro. It can also delay the onset of disease and reduce the severity of the disease to some extent. Gene therapy has achieved remarkable success in human and animal models of various retinal diseases. The eye is a particularly suitable organ for gene therapy, and in addition, Single and low dose administration and ocular immunity immunity can reduce immunogenicity, and the mild host immune response caused by intraocular injection is not toxic to the retina. In many organ adeno-associated virus (AAVV) mediated clinical gene therapy trials have been passed, but only a few studies in the EAU model. In this study, We successfully injected AAV2 vector virus particles carrying mIL-27p28 gene into the intraocular retina of B10RIII mice. The results showed that p28 expressed at a stable high concentration in the eyes and significantly inhibited the degree of EAU inflammation. The inhibitory effect was also found to be associated with down-regulation of IL-17 expression and up-regulation of intraocular IL-10 expression.
【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R773;R-332

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