本文關(guān)鍵詞： 猴免疫缺陷病毒 中醫(yī)證候 藥物療法 長(zhǎng)期不進(jìn)展型　出處：《廣州中醫(yī)藥大學(xué)》2015年博士論文　論文類型：學(xué)位論文

【摘要】：目的：評(píng)價(jià)健脾補(bǔ)腎解毒法中藥對(duì)猴艾滋病的干預(yù)效果；探討猴艾滋病模型不同類型的進(jìn)展風(fēng)險(xiǎn)影響因素；探索猴艾滋病模型長(zhǎng)期不進(jìn)展型的內(nèi)在病理機(jī)制；方法：第一章健脾補(bǔ)腎解毒法中藥治療猴艾滋病模型的效果選用同期感染的、基線狀態(tài)相當(dāng)?shù)?只艾滋病恒河猴,隨機(jī)分為兩組,分別進(jìn)行連續(xù)8周的中藥和抗病毒藥治療,定期采血和采集腹股溝淺表淋巴結(jié),實(shí)驗(yàn)結(jié)束進(jìn)行胃腸道粘膜的標(biāo)本采集。檢測(cè)T細(xì)胞純真亞群、記憶亞群、功能亞群,腸淋巴歸巢受體等免疫指標(biāo)；血漿病毒載量及組織中SIVRNA和SIVDNA等病毒學(xué)指標(biāo)；以及中醫(yī)證候指標(biāo)和病理學(xué)結(jié)構(gòu)的檢測(cè),分析比較了中藥組和抗病毒藥組在治療過程中各指標(biāo)的差異。第二章猴艾滋病模型不同類型的進(jìn)展風(fēng)險(xiǎn)影響因素探討挑選符合長(zhǎng)期不進(jìn)展型(LTNP)、一般進(jìn)展型(NP)、快速進(jìn)展型(RP)特點(diǎn)的三種類型恒河猴各10只,與同期5只健康恒河猴對(duì)比,分析感染前后不同類型間T細(xì)胞亞群、中醫(yī)證候指標(biāo)及淋巴結(jié)病理的不同之處。找出不同類型進(jìn)展風(fēng)險(xiǎn)的影響因素,并建立判別方程對(duì)其風(fēng)險(xiǎn)進(jìn)行預(yù)測(cè)。第三章探索猴艾滋病模型長(zhǎng)期不進(jìn)展型的內(nèi)在病理機(jī)制選入長(zhǎng)期不進(jìn)展型艾滋病恒河猴4只,同期進(jìn)入試驗(yàn)的3只正常猴(Normal)和4只一般進(jìn)展型(NP) SIV猴,作為對(duì)照,連續(xù)觀察6個(gè)月,觀察期間三組均不進(jìn)行任何干預(yù)。定期采血和采集腹股溝淺表淋巴結(jié),實(shí)驗(yàn)結(jié)束進(jìn)行胃腸道粘膜的標(biāo)本采集。檢測(cè)T細(xì)胞純真亞群、記憶亞群、功能亞群,腸淋巴歸巢受體等免疫指標(biāo)；血漿病毒載量及組織中SIVRNA和SIVDNA等病毒學(xué)指標(biāo)；以及中醫(yī)證候指標(biāo)和病理學(xué)結(jié)構(gòu)的檢測(cè),分析比較三組各指標(biāo)的差異。結(jié)果：第一章健脾補(bǔ)腎解毒法中藥治療猴艾滋病模型的效果健脾補(bǔ)腎解毒法中藥治療雖然不能像HAART一樣明顯降低血漿和細(xì)胞內(nèi)的SIVDNA/RNA,但可以升高外周血的CD4。該亞群主要為CD4純真細(xì)胞；同時(shí)表達(dá)CD28上調(diào)、CCR5下調(diào)、β7+及CCR9明顯增加。胃腸道粘膜內(nèi)β7+及CCR9的表達(dá)卻明顯降低。這一改變,可能與MAVS蛋白下降存在某些關(guān)聯(lián)。此外在一定程度上延緩了脾虛的出現(xiàn)和發(fā)展,相比HAART組,淋巴結(jié)病理結(jié)構(gòu)保存更完整,均顯示了健脾補(bǔ)腎解毒法中藥有相當(dāng)?shù)呐R床價(jià)值。第二章猴艾滋病模型不同類型的進(jìn)展風(fēng)險(xiǎn)影響因素探討1各組動(dòng)物血漿病毒載量均在感染后10-14天達(dá)到高峰,平臺(tái)期出現(xiàn)分化。2與Normal相比,RP型的WBC明顯偏高,CD4和LYM比例明顯偏低；而LTNP型的LYM數(shù)量偏高；3與其它類型相比,RP型的β2-MG顯著升高,T3顯著降低。4 RP型在平臺(tái)期出現(xiàn)淋巴結(jié)縮小,生發(fā)中心明顯縮小的退變型,區(qū)別于其它各型。感染前WBC和LYM比例進(jìn)入判別方程,平臺(tái)期為T4和平臺(tái)期LoglORNA進(jìn)入判別方程,對(duì)所建立的判別函數(shù)的一致率進(jìn)行檢驗(yàn),感染前和平臺(tái)期理論判別與實(shí)際資料的總吻合率分別為57.1%和91.2%。第三章探索猴艾滋病模型長(zhǎng)期不進(jìn)展型的內(nèi)在病理機(jī)制LTNP組的血漿病毒載量情況、CD4數(shù)量、比例和記憶亞群、功能亞群均符合我們的預(yù)期,指標(biāo)大多介于NP組和正常組之間,此外我們發(fā)現(xiàn)LTNP組淋巴結(jié)中CCR5低表達(dá),趨化于腸粘膜效應(yīng)部位因子的T細(xì)胞更高、且更接近于正常組。這可能是LTNP的重要特征、甚至參與了LTNP的形成。而作為病毒核酸受體TLR、RLR家族共同接頭信號(hào)蛋白的MAVS在LTNP明顯低于NP組,可能使得LTNP淋巴結(jié)中炎性細(xì)胞因子較低,從而降低了淋巴細(xì)胞的活化,進(jìn)而延緩了疾病進(jìn)程,使得LTNP猴天然感染SIV病毒載量很低。各指標(biāo)都表明LTNP處在一種相對(duì)穩(wěn)定狀態(tài),而非普通SIV感染處于的活化過度狀態(tài)。結(jié)論：1 該方藥可以升高CD4純真細(xì)胞；同時(shí)表達(dá)CD28上調(diào)、CCR5下調(diào)、β7及CCR9明顯增加,而且淋巴結(jié)病理結(jié)構(gòu)保存更完整,有一定的臨床價(jià)值和應(yīng)用前景。2 LTNP、NP和RP三種進(jìn)展類型在平臺(tái)期有明顯差異,其中RP型有更明顯的脾腎俱虛證候,提示脾腎俱虛有可能是艾滋病快速進(jìn)展的關(guān)鍵因素。另外,感染前的WBC和LYM比例可作為評(píng)價(jià)不同進(jìn)展類型的一個(gè)參考,而平臺(tái)期的LoglORNA和T4可用于預(yù)測(cè)不同類型進(jìn)展的風(fēng)險(xiǎn)。3 LTNP各方面指標(biāo)介于Normal和NP之間,甚至更偏向于Normal。淋巴結(jié)中CCR5低表達(dá),趨化于腸粘膜效應(yīng)部位因子的T細(xì)胞更高、且更接近于正常組,而作為病毒核酸受體TLR、RLR家族共同接頭信號(hào)蛋白的MAVS在LTNP明顯低,可能使得LTNP淋巴結(jié)中炎性細(xì)胞因子較低,降低了淋巴細(xì)胞的活化及疾病進(jìn)程。這些都可能參與了LTNP的形成,使得LTNP猴天然感染SIV很低。
[Abstract]:Objective: To evaluate the intervention effects of Jianpi Bushen herbs on detoxification of simian AIDS; risk factors in the impact of different types of monkey model of AIDS; explore the internal pathogenesis of simian AIDS type model of long-term development; methods: the period of the first chapter of the infection effect of spleen and kidney detoxification method of Chinese medicine treatment of AIDS monkey model, a baseline the 8 Ganges RIver AIDS monkeys were randomly divided into two groups, respectively, Chinese medicine and antiviral therapy for 8 weeks, and regular blood collection of inguinal superficial lymph node, the end of the experiment specimens of the gastrointestinal mucous membrane. The detection of T cell subsets in pure, memory subsets, functional subsets of intestinal lymphatic homing receptor immune index; plasma viral load of SIVRNA and SIVDNA and the amount of tissue such as virology index; and TCM syndrome index and pathological structure of the detection, analysis and comparison of Chinese Medicine The difference of each index group and antiviral group in the treatment process. The second chapter simian AIDS model factors in the risk of the effects of different types of selected in line with the long term nonprogressors type (LTNP), the general progress of type (NP), rapidly progressive (RP) characteristics of Ganges RIver three types of monkey by 10, and 5 in the same period healthy Ganges RIver monkey comparative analysis before and after infection among different types of T cell subsets, different TCM syndrome index and lymph node pathology. To find out the influencing factors of different types of risk, and establish the discriminant equation to predict the risk. The third chapter explores the intrinsic mechanism of pathological model of simian AIDS type selected for long-term progress the long-term progress of AIDS in Ganges RIver 4 monkeys, 3 normal monkeys into the test period (Normal) and 4 (NP) in general SIV monkey, as control, continuous observation for 6 months, during the observation period, three groups were regularly without any intervention. Blood collection and inguinal superficial lymph node, the end of the experiment were collected of the gastrointestinal mucosa. Detection of T cell subsets in pure, memory subsets, functional groups, intestinal lymphoid homing receptor immune index; plasma viral load of SIVRNA and SIVDNA and the amount of tissue such as virology index; and TCM syndrome index and pathology the structure of the detection, analysis and comparison of each index in three groups. Results: the effect of traditional Chinese medicine of invigorating the spleen and kidney detoxification method of the first chapter of invigorating the spleen and kidney detoxification method of traditional Chinese medicine in the treatment of AIDS treatment although not monkey model like HAART significantly decreased the plasma and intracellular SIVDNA/RNA, but can increase the peripheral blood CD4. of the main CD4 cell subsets of innocence at the same time; increase the expression of CD28, CCR5 and CCR9 reduced, beta 7+ increased significantly. The expression of 7+ beta and CCR9 in gastrointestinal mucosa decreased obviously. This change, there may be some close down and MAVS protein In addition to delay the spleen. The emergence and development to a certain extent, compared with HAART group, lymph node pathology showed more complete preservation, Jianpi Bushen Jiedu method has clinical value. The second chapter is the factors in the risk of simian AIDS model the impact of different types of the discussion in 1 groups of animal plasma viral load in the peak at 10-14 days after infection, the platform differentiation.2 compared with Normal, RP WBC and LYM CD4 were high, the proportion is significantly lower; and the LTNP type LYM high number; 3 compared with other types, RP type beta 2-MG increased significantly, T3 decreased significantly.4 RP type lymph nodes on the platform period of degeneration of the germinal center was significantly reduced, different from other type. WBC and LYM before infection proportion into the discriminant equation. Platform for T4 and LoglORNA platform into the discriminant equation. The discriminant function of the consistent rate Test before infection and the platform theory is consistent with the actual data of the total discrimination rate was LTNP internal pathogenesis group plasma virus 57.1% and 91.2%. the third chapter explore the monkey model of AIDS long-term progressive load, CD4 number, proportion and memory subsets, subsets are in line with our expectations, between the index mostly between NP group and normal group, in addition we found LTNP lymph node in CCR5 low expression of chemotactic factor on intestinal mucosal effector T cells more and more close to the normal group. This may be an important feature of LTNP, and even participate in the formation of LTNP. As the viral nucleic acid receptor TLR, RLR family common joint signal protein MAVS in LTNP was significantly lower than that of NP group, so LTNP lymph node inflammatory cytokines is low, thereby reducing the lymphocyte activation, and thus delay the progress of the disease, the natural LTNP monkey SIV virus infection The load is very low. The index shows that LTNP in a relatively stable state, rather than the common SIV infection is the excessive activation state. Conclusion: the recipe can increase 1 pure CD4 cells; while CD28 expression increased, CCR5 reduced, beta 7 and CCR9 increased significantly, and the lymph node pathological structure more complete preservation that has clinical value and application prospect of.2 LTNP, there are obvious differences in the platform NP and RP three in type, the RP type has more obvious inherent deficiency syndromes of spleen and kidney, spleen and kidney are all hollow tips may be the key factor in the rapid HIV infection. In addition, before the WBC and LYM ratio can be used as a reference to the evaluation of different types of progress, while the platform of LoglORNA and T4 can be used to predict the progress of different types of risk indexes of LTNP.3 between Normal and NP, and even more biased in favor of CCR5 Normal. in lymph nodes of low expression of chemoattractant in the intestinal mucosa. Should part factor in T cell is higher, and more close to the normal group, as the viral nucleic acid receptor TLR, RLR family protein MAVS connector signal in LTNP was significantly lower, may make LTNP lymph node inflammatory cytokines in low reduced lymphocyte activation and progression of the disease. These may be involved in LTNP the formation of the natural infection of SIV LTNP monkey is very low.

【學(xué)位授予單位】：廣州中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R285.5;R-332

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