【摘要】：目的:本課題探討子宮內(nèi)膜再生細(xì)胞(ERC)在潰瘍性結(jié)腸炎(UC)小鼠模型中免疫調(diào)節(jié)的作用及相關(guān)機(jī)制。自經(jīng)血中分離鑒定ERC,觀察其表面程序性死亡受體-配體1(PD-L1)的表達(dá)情況;建立UC的小鼠動(dòng)物模型;探討ERC在UC小鼠模型體內(nèi)的分布情況;將ERC應(yīng)用于UC的體內(nèi)體外實(shí)驗(yàn),研究ERC細(xì)胞表面的PD-L1免疫調(diào)節(jié)分子在UC治療中的作用。方法:1)以月事杯收集健康育齡期女性志愿者的月經(jīng)血,利用標(biāo)準(zhǔn)的Ficoll方法分離月經(jīng)血樣品中的單個(gè)核細(xì)胞,進(jìn)行細(xì)胞培養(yǎng),應(yīng)用流式細(xì)胞術(shù)鑒定ERC的表面抗原。2)選用SPF級(jí)的BALB/c小鼠,將其飲用不同濃度的葡聚糖硫酸鈉(DSS)溶液建立UC小鼠動(dòng)物模型,觀察造模期間實(shí)驗(yàn)動(dòng)物的一般情況、疾病活動(dòng)指數(shù)(DAI)及組織病理學(xué)改變,選擇最佳的DSS濃度并對(duì)小鼠動(dòng)物模型進(jìn)行評(píng)估。3)應(yīng)用PKH26(Paul Karl Horan 26)對(duì)ERC進(jìn)行體外標(biāo)記,將標(biāo)記后的ERC應(yīng)用于UC動(dòng)物模型,觀察ERC在UC動(dòng)物模型體內(nèi)的分布情況。4)應(yīng)用PD-L1抗體對(duì)ERC細(xì)胞表面的PD-L1進(jìn)行封閉,在體內(nèi)實(shí)驗(yàn)中,將ERC及PD-L1抗體封閉后的ERC應(yīng)用于UC動(dòng)物模型(分為四組,(1)正常對(duì)照組:自由飲用不含DSS的飲用水;(2)未治療組:自由飲用3%DSS溶液+經(jīng)靜脈注射PBS緩沖液;(3)ERC組:自由飲用3%DSS溶液+靜脈注射以PBS緩沖液重懸的ERC;(4)PD-L1封閉的ERC組:自由飲用3%DSS溶液+靜脈注射以PBS緩沖液重懸的PD-L1封閉的ERC),第2、5、8天,ERC組經(jīng)尾靜脈注射ERC(1×106/0.2ml/只),PD-L1封閉的ERC組經(jīng)尾靜脈注射PD-L1封閉的ERC(1×106/0.2ml/只),第8天,所有組均改為飲用水,實(shí)驗(yàn)期間每天觀察并記錄各組實(shí)驗(yàn)動(dòng)物的一般狀況,進(jìn)行DAI評(píng)分,第15天,處死全部小鼠,測(cè)量自然狀態(tài)下結(jié)直腸長度,顯微鏡下觀察結(jié)直腸的病理改變,采用流式細(xì)胞術(shù)檢測(cè)脾臟CD3~+CD4~+T、CD3~+CD8~+T、CD4~+CD25~+Foxp3~+Tregs、CD11c~+MHC-II~+DCs、F4/80~+M、F4/80~+CD206~+M細(xì)胞數(shù)量;采用ELISA及q PCR的方法檢測(cè)結(jié)直腸正常組織及病變組織TNF-α、IFN-γ、IL-10、TGF-β的蛋白水平及m RNA轉(zhuǎn)錄水平。在體外實(shí)驗(yàn)中,從正常小鼠中分離脾細(xì)胞,將ERC與脾細(xì)胞進(jìn)行共培養(yǎng)或者將PD-L1封閉的ERC與脾細(xì)胞進(jìn)行共培養(yǎng),應(yīng)用不同的細(xì)胞刺激因子對(duì)脾細(xì)胞進(jìn)行刺激(分為四組,(1)未治療組:單純脾細(xì)胞培養(yǎng);(2)ERC治療組:ERC與脾細(xì)胞進(jìn)行共培養(yǎng);(3)PD-L1封閉的ERC治療組:PD-L1封閉的ERC與脾細(xì)胞進(jìn)行共培養(yǎng);(4)transwell培養(yǎng)組:ERC與脾細(xì)胞進(jìn)行非接觸的共培養(yǎng)),應(yīng)用流式細(xì)胞術(shù)分析不同組中CD3~+CD4~+T、CD3~+CD8~+T、CD4~+CD25~+Foxp3~+Tregs、CD11c~+MHC-II~+DCs、F4/80~+M、F4/80~+CD206~+M細(xì)胞的數(shù)量;分析上述指標(biāo)的變化,評(píng)價(jià)PD-L1在ERC治療小鼠UC中的作用。結(jié)果:1)ERC能夠表達(dá)PD-L1、CD90、CD105,不表達(dá)CD34、CD45;隨著刺激因子IFN-γ濃度的增加,ERC表面的PD-L1表達(dá)相應(yīng)增加。2)隨著DSS濃度的增加及造模時(shí)間的延長,造模小鼠的一般狀況逐漸變差、進(jìn)食進(jìn)水逐漸減少、體重逐漸下降、DAI評(píng)分逐漸增加,小鼠的病死率增加,其病理學(xué)改變包括:粘膜固有層中性粒細(xì)胞、巨噬細(xì)胞、淋巴細(xì)胞的浸潤,腺窩扭曲變形,固有層增厚,粘膜下層淋巴濾泡形成,小鼠腸道的炎癥逐漸加重。3)將PKH26熒光標(biāo)記的ERC于造模第5天經(jīng)尾靜脈注入U(xiǎn)C小鼠動(dòng)物模型體內(nèi),在ERC注入48h時(shí)進(jìn)行組織取材,熒光顯微鏡觀察顯示熒光強(qiáng)度為肺臟肝臟脾臟結(jié)腸組織,腎臟沒有觀察到熒光,模型組結(jié)直腸病變組織熒光強(qiáng)度高于正常組結(jié)直腸組織的熒光強(qiáng)度。4)體內(nèi)實(shí)驗(yàn)顯示,尾靜脈注射ERC對(duì)小鼠結(jié)直腸炎癥有明顯的保護(hù)作用,封閉ERC表面的PD-L1明顯降低ERC對(duì)小鼠的結(jié)直腸炎癥保護(hù)作用;與未治療組比較,ERC組脾臟CD3~+CD4~+T、CD3~+CD8~+T細(xì)胞數(shù)量明顯減少(P0.05),CD4~+CD25~+Foxp3~+Tregs細(xì)胞數(shù)量明顯增加(P0.05),CD11c~+MHC-II~+DCs細(xì)胞數(shù)量顯著減少(P0.05),F4/80~+M細(xì)胞數(shù)量明顯減少(P0.05),F4/80~+CD206~+M相對(duì)增加(P0.05),結(jié)直腸病變組織內(nèi)TNF-α、IFN-γ的m RNA轉(zhuǎn)錄水平及蛋白表達(dá)水平降低(P0.05),IL-10、TGF-β的m RNA轉(zhuǎn)錄水平及蛋白表達(dá)水平升高(P0.05);與ERC組相比,PD-L1封閉的ERC治療組脾臟CD3~+CD4~+T、CD3~+CD8~+細(xì)胞數(shù)量相對(duì)增加(P0.05)、CD4~+CD25~+Foxp3~+Tregs細(xì)胞數(shù)量相對(duì)減少(P0.05)、CD11c~+MHC-II~+DCs細(xì)胞數(shù)量相對(duì)增加(P0.05),結(jié)直腸組織內(nèi)TNF-α、IFN-γ的m RNA轉(zhuǎn)錄水平及蛋白表達(dá)水平相對(duì)增加(P0.05),IL-10、TGF-β的m RNA轉(zhuǎn)錄水平及蛋白表達(dá)水平相對(duì)減少(P0.05)。體外實(shí)驗(yàn)顯示,與正常對(duì)照組相比,經(jīng)不同的刺激因子刺激后,ERC共培養(yǎng)組CD3~+CD4~+T、CD3~+CD8~+T、CD11c~+MHC-II~+DCs、F4/80~+M細(xì)胞數(shù)量相對(duì)減少,CD4~+CD25~+Foxp3~+Tregs、F4/80~+CD206~+M細(xì)胞數(shù)量相對(duì)增加;PD-L1封閉的ERC共培養(yǎng)組與ERC共培養(yǎng)組相比,CD3~+CD4~+T、CD3~+CD8~+T、CD11c~+MHC-II~+DCs、F4/80~+M細(xì)胞數(shù)量相對(duì)增加,CD4~+CD25~+Foxp3~+Tregs、F4/80~+CD206~+M細(xì)胞數(shù)量相對(duì)減少;transwell培養(yǎng)組與ERC共培養(yǎng)組相比,CD3~+CD4~+T、CD3~+CD8~+T、CD11c~+MHC-II~+DCs、F4/80~+M細(xì)胞數(shù)量相對(duì)增加,CD4~+CD25~+Foxp3~+Tregs、F4/80~+CD206~+M細(xì)胞數(shù)量相對(duì)減少。結(jié)論:1)自經(jīng)血中分離的ERC是一種類似于MSC的再生細(xì)胞,ERC不但來源豐富、獲取無創(chuàng),而且ERC表面表達(dá)在誘導(dǎo)免疫耐受方面發(fā)揮重要作用的免疫調(diào)節(jié)分子PD-L1。2)3%的DSS為構(gòu)建BALB/c小鼠UC動(dòng)物模型的理想濃度,該濃度不但能夠很好的模擬人UC腸道病理改變,而且沒有小鼠的病死發(fā)生。3)將ERC通過小鼠尾靜脈注入U(xiǎn)C模型小鼠體內(nèi)后,ERC能夠向腸道炎癥部位遷移,而且ERC在腸道的分布高于正常對(duì)照組。4)PD-L1在ERC有效控制UC動(dòng)物模型腸道炎癥的發(fā)生發(fā)展中發(fā)揮重要作用,體內(nèi)體外實(shí)驗(yàn)均顯示ERC通過PD-L1抑制DCs的成熟分化及CD4~+T和CD8~+T細(xì)胞的增殖、促進(jìn)Tregs細(xì)胞及M2細(xì)胞的產(chǎn)生,并且體外實(shí)驗(yàn)中還顯示ERC表面的PD-L1通過直接接觸的方式起作用,進(jìn)而發(fā)揮免疫調(diào)節(jié)的作用。
[Abstract]:Objective: To investigate the role of endometrial regeneration cells (ERC) in the immune regulation of mice with ulcerative colitis (UC) and its related mechanism. Methods: 1) The menstrual blood of healthy female volunteers of childbearing age was collected with a menstrual cup, and the mononuclear cells were isolated by standard Ficoll method. The cells were cultured and identified by flow cytometry. To determine the surface antigen of ERC. 2) SPF BALB / c mice were used to establish UC mice model by drinking different concentrations of sodium dextran sulfate (DSS) solution. The general conditions, disease activity index (DAI) and histopathological changes of the experimental animals were observed during the modeling period. The best concentration of DSS was selected and the animal model was evaluated. 3) The animal model was established by P KH26 (Paul Karl Horan 26) was used to label ERC in vitro. The labeled ERC was applied to UC animal model to observe the distribution of ERC in vivo. 4) PD-L1 antibody was used to block the surface of ERC cells. In vivo, ERC blocked by ERC and PD-L1 antibody was applied to UC animal model (divided into four groups: (1) Normal. Control group: free drinking water without DSS; (2) untreated group: free drinking 3% DSS solution + intravenous PBS buffer; (3) ERC group: free drinking 3% DSS solution + intravenous PBS buffer suspension of ERC; (4) PD-L1 blocked ERC group: free drinking 3% DSS solution + intravenous PBS buffer suspension of PD-L1 blocked ERC, 2, 5, 8 On the 8th day, all groups were changed to drinking water. During the experiment, the general condition of experimental animals in each group was observed and recorded daily, and the DAI score was made. On the 15th day, all the mice were sacrificed. Colon length, colon pathological changes were observed under microscope, CD3~+CD4~+T, CD3~+CD8~+T, CD4~+CD25~+Foxp3~+Tregs, CD11c~+MHC-II~+DCs, F4/80~+CD206~+M cells in spleen were detected by flow cytometry, and TNF-a, IFN-gamma, IL-10, TGF-beta in normal and pathological tissues were detected by ELISA and q-PCR. In vitro, spleen cells were isolated from normal mice, and ERC was co-cultured with spleen cells or PD-L1-blocked ERC was co-cultured with spleen cells. Splenocytes were stimulated with different cytokines (divided into four groups: (1) untreated group: spleen cells were cultured alone; (2) ERC treatment group: ERC and spleen Cells were co-cultured; (3) PD-L1-blocked ERC treatment group: PD-L1-blocked ERC and spleen cells were co-cultured; (4) Transwell culture group: ERC and spleen cells were co-cultured without contact, using flow cytometry analysis of CD3~+CD4~+T, CD3~+CD8~+T, CD4~+CD25~+Foxp3~+Tregs, CD11c~+MHC-II~+DCs, F4/80~+M, F4/80~+M, CD206~+ cells in different groups. Results: 1) ERC could express PD-L1, CD90, CD105, but not CD34 and CD45; with the increase of IFN-gamma concentration, the expression of PD-L1 on the surface of ERC increased correspondingly. 2) With the increase of DSS concentration and the prolongation of modeling time, the general condition of model mice increased gradually. Pathological changes include: the infiltration of neutrophils, macrophages, lymphocytes, pits distorted, lamina propria thickened, lymphatic follicles formed in submucosa, intestinal inflammation aggravated gradually. 3) PK H26 fluorescence labeled ERC was injected into UC mice by tail vein on the 5th day of modeling. The tissues were taken at 48h of ERC injection. Fluorescence microscopy showed that the fluorescence intensity was lung, liver, spleen, colon, kidney and no fluorescence was observed. The fluorescence intensity of colorectal lesions in model group was higher than that in normal group. LIGHT INTENSITY.4) In vivo, caudal vein injection of ERC had significant protective effect on colorectal inflammation in mice, and blocked surface of ERC by PD-L1 significantly decreased the protective effect of ERC on colorectal inflammation in mice. Compared with untreated group, the number of splenic CD3~+CD4~+T, CD3~+CD8~+T cells and CD4~+CD25~+Foxp3~+Tregs cells in ERC group decreased significantly (P 0.05), and the number of CD4~+CD25~+Foxp3 The number of CD11c~+MHC-II~+DCs decreased significantly (P 0.05), F4/80~+M cells decreased significantly (P 0.05), F4/80~+CD206~+M increased relatively (P 0.05), TNF-a, IFN-gamma m RNA transcription and protein expression decreased (P 0.05), IL-10, TGF-beta m RNA transcription and protein expression increased in colorectal lesions. Compared with the ERC group, the number of CD3~+CD4~+T, CD3~+CD8~+ cells in spleen and CD4~+CD25~+Foxp3~+Tregs cells in PD-L1-blocked ERC group increased (P 0.05), the number of CD4~+CD25~+Foxp3~+Tregs cells decreased (P 0.05), the number of CD11c~+MHC-II~+DCs cells increased (P 0.05), the level of TNF-a, IFN-gamma m RNA transcription and protein expression in colorectal tissues increased relatively. Compared with the normal control group, the number of CD3~+CD4~+T, CD3~+CD8~+T, CD11c~+MHC-II~+DCs, F4/80~+M cells and the number of CD4~+CD25~+Foxp3~+Tregs, F4/80~+M cells in ERC co-culture group were decreased after stimulation with different stimuli. The number of CD3 + CD4 + T, CD3 + CD4 + T, CD3 + CD8 + T, CD11c + MHC - II + DCs, F4 / 80 + M cells were relatively increased, CD4 + CD25 + Foxp3 + Tregs, F4 / 80 + Tregs, F4 / 80 + CD206 + M cells were relatively decreased; the number of CD3 + CD3 + CD4 + CD4 + CD4 + CD4 + T, CD3 + CD3 + CD3 + CD3, CD3 + CD3 + CD3 + CD8 + CD8 + CD8 + CD8 + CD8 + DCs, CD11c + MHC - II + DCs, F4 / 80 + M cells were relatively increased, CD4 + CD4 + CD4 + CD4 + CD25 + CD25 + Foxp3 + Tregs, F4 / 80 + CD80 s, F4/ The number of CD4~+CD25~+Foxp3~+Tregs and F4/80~+CD206~+M cells were relatively decreased. CONCLUSION: 1) ERC isolated from menstrual blood is a kind of MSC-like regenerative cells. ERC is not only abundant in source, but also noninvasive, and the expression of ERC on the surface plays an important role in inducing immune tolerance PD-L1.2) 3%. DSS is an ideal concentration for constructing UC animal model of BALB/c mice. It can not only simulate the pathological changes of human UC intestine, but also has no mortality in mice. In vivo and in vitro experiments showed that ERC inhibited the maturation and differentiation of DCs and the proliferation of CD4~+T and CD8~+T cells, promoted the production of Tregs cells and M2 cells, and in vitro experiments also showed that PD-L1 on the surface of ERC acted through direct contact. And then play the role of immunomodulation.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R574.62;R-332

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