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题名	氯喹对pDC激活的抑制及其对AIDS发病进程影响机制研究
作者	马建平
学位类别	硕士
答辩日期	2011-05
授予单位	中国科学院研究生院
授予地点	北京
导师	郑永唐
关键词	AIDS HIV-1 SIV 免疫激活 pDC 氯喹 中国恒河猴
学位专业	生物化学与分子生物学
中文摘要	氯喹对pDC激活的抑制及其对AIDS发病进程影响机制研究 本论文研究由2个相互联系又相对独立的部分组成：慢性期与晚期SIV感染中国恒河猴免疫激活差异研究；氯喹对pDC激活的抑制及其对AIDS发病进程影响机制研究。 近年来的研究结果认为，在HIV感染期持续的非特异免疫激活与CD4+T 细胞的大量损失和艾滋病发病过程密切相关。但是，导致体内免疫激活的确切机制目前尚不清楚。很多研究人员倾向于认为在慢性感染期，血液中高含量的HIV病毒颗粒是造成免疫激活的主要原因。HIV作为单链RNA病毒，可以被pDC经细胞吞噬作用吞入其内体，之后被表达于内体上的TLR7和TLR9识别并引发下游信号转导，产生大量的I型干扰素。I型干扰素持续性以高水平存在，导致对CD4+T细胞、CD8+ T细胞和单核细胞的非特异激活并影响各亚群细胞的表型、功能和其寿命，从而导致艾滋病进展的加速。此外，有实验表明，体内高水平的LPS可能也是HIV感染过程中持续的免疫激活的重要因素。因此，对免疫激活机制进行深层次研究有助于揭示AIDS的发病机制和制定有效地临床治疗方案。 我们实验室已建立了标准的SIVmac239感染中国恒河猴AIDS动物模型，可以作为AIDS发病机制研究的有力工具。为了寻找免疫激活对SIV感染的中国恒河猴的影响机制。我们分别检测了SIV慢性感染期和晚期以及SIV阴性中国恒河猴免疫激活的差异。研究发现：SIV感染可以导致pDC的激活，同时伴随着CD4+T细胞的激活和凋亡水平的增加。很有趣的是，我们的实验结果显示，晚期感染的中国恒河猴免疫激活较慢性感染期严重，从而为病毒导致的pDC免疫激活对AIDS进程的促进作用的观点提供了支持。 同时，我们通过实验验证了氯喹在体外和体内水平抑制pDC激活的作用。氯喹作为碱性物质，可以通过渗透进入细胞内体，抑制内体的酸化和成熟来阻断病毒RNA通过TLR7和TLR9引发的的信号通路，从而抑制pDC的活化和I型干扰素的分泌。我们发现氯喹体外抑制TLR7和TLR9的配体对pDC的激活及I型干扰素的分泌作用明显。通过30天的灌胃给药，我们发现氯喹可以有效地抑制pDC激活，但是对T细胞的激活和数量变化以及病毒载量影响较小。 本论文研究为免疫激活对艾滋病进展的作用机制提供了数据，同时验证了氯喹作为免疫激活抑制剂成为抗AIDS药物的潜在价值，对AIDS的发病机制和临床治疗研究具有重要意义。
英文摘要	The inhibition of chloroquine on pDC activation and its role in the disease progression in the SIV infected Chinese rhesus macaques In this dissertation, two independent parts are included: late SIVmac239 infected Chinese rhesus macaques showed high immune activation; the inhibition of chloroquine on the pDC activation and its role in the disease progression in the SIV infected Chinese rhesus macaques. In the recent several years, it is widely accepted the immune activation contribute a great deal to the severe loss of the CD4+ T cells and the progression to AIDS in the HIV infected individuals. However, the mechanism which leads to this obvious immune activation during HIV infection remains indistinct. Experimental data from many laboratories suggested the activation of the pDCs by the plasma viremia may play a critical role in the immune activation. The HIV can be identified by the Toll like receptor 7 or 9 in the pDCs after its entry into the endosoma through endocytosis. Then the subsequent factors interact with the TLR7/9 and turn on the TLR pathway. At last, the plasmacytoid dendritic cells were activated and large numbers of the type-I interferon are secreted. These high levels of the IFN-I can stimulate the CD4+ T cells, CD8+ T cells, monocytes and other important cell subsets of the immune system which showed an activation phenotype subsequently. The impact of the IFN-I may include the functions, lives and other important properties of the targeted cells. Then, it leads to the rapid progression to AIDS. In addition, there are also many researchers considering the high levels of LPS during HIV infection may be one important cause of the immune activation. As a result, a deep understand of the relationship between immune activation and AIDS may help us to investigate the mechanisms of AIDS and develop effective therapy strategies against it. Our laboratory has established the SIV infected Chinese rhesus macaques as a standard non-human primate AIDS model which can be used to investigate the mechanisms of AIDS. In this study, we have investigated the SIVmac239 infected Chinese rhesus macaques had a higher immune activation phenotype compared with the control animals. The activation of pDC and T cells and also the apoptosis level of T lymphocytes became more severe in the late SIV infected macaques, which suggested the immune activation may lead to the rapid progression to AIDS. We evaluated the immune activation inhibiting function of chloroquine in vitro and in vivo.Chloroquine can block the TLR mediated pDC activation by inhibiting the acidification of the endosome in pDC. Our work clearly showed the chloroquine could effectively inhibit the pDC activation and alpha-IFN production mediated by TLR ligands and the concentrated SIV viral particles. However, there were no evident differences in the T cell activation and the viral load after 30 days chloroquine treatment on the SIVmac239 infected Chinese rhesus macaques. Our work provides valuable data for the research on the mechanism of AIDS and we also tested the validity of chloroquine to be used as an effective drug due to its potential function to inhibit the pDC activation. Our work has a valuable contribution to the further investigation of AIDS mechanisms and its clinical therapy strategies. Keywords: AIDS; HIV-1; SIV; immune activation; pDC; chloroquine; Chinese rhesus macaques
语种	中文
公开日期	2011-08-26
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/353002/6724]
专题	昆明动物研究所_分子免疫药理学
推荐引用方式 GB/T 7714	马建平. 氯喹对pDC激活的抑制及其对AIDS发病进程影响机制研究[D]. 北京. 中国科学院研究生院. 2011.

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