本文關(guān)鍵詞：補(bǔ)體C3對(duì)同種異基因移植排斥中Th17細(xì)胞應(yīng)答的調(diào)控機(jī)制研究　出處：《第三軍醫(yī)大學(xué)》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 同種異基因移植排斥 補(bǔ)體C3 Th17細(xì)胞 Tregs

【摘要】：移植是治療器官功能衰竭的有效手段,移植排斥反應(yīng)是移植物丟失的主要原因。CD4+T細(xì)胞是介導(dǎo)移植排斥反應(yīng)的重要細(xì)胞,不同CD4+T細(xì)胞亞群在移植排斥反應(yīng)中功能各不相同。Th1及Th17細(xì)胞加速移植排斥,而Th2及Treg細(xì)胞則誘導(dǎo)移植物耐受。目前廣泛使用的免疫抑制藥物,如環(huán)孢素A、FK506及雷帕霉素等,通過(guò)抑制整個(gè)T細(xì)胞亞群的增殖分化來(lái)調(diào)控移植排斥反應(yīng),存在明顯的局限性。因此,發(fā)展選擇性抑制T細(xì)胞亞群的新型免疫抑制劑是未來(lái)抗排斥藥物研究的方向。研究移植狀態(tài)下T細(xì)胞亞群分化調(diào)節(jié)機(jī)制,對(duì)于理解移植排斥反應(yīng)病理生理和發(fā)展選擇性干預(yù)T細(xì)胞的抗排斥反應(yīng)藥物具有十分重要的意義。Th17是CD4+T細(xì)胞的重要亞群,因主要分泌細(xì)胞因子IL-17得名。IL-17可向炎癥部位募集大量單核細(xì)胞、中性粒細(xì)胞或與其它炎癥因子共同作用參與調(diào)節(jié)免疫炎癥反應(yīng)。Th17細(xì)胞在過(guò)敏性哮喘、糖尿病、銀屑病、SLE及移植排斥反應(yīng)中具有重要作用。研究發(fā)現(xiàn),Th17細(xì)胞局部浸潤(rùn)與移植腎功能及腎組織損傷的嚴(yán)重程度顯著相關(guān)。運(yùn)用特異性抗體阻斷IL-17A,小鼠移植肺中淋巴細(xì)胞及IFN-γ陽(yáng)性細(xì)胞浸潤(rùn)顯著降低,且阻塞性支氣管炎顯著緩解。研究移植狀態(tài)下Th17細(xì)胞分化調(diào)控機(jī)制,對(duì)開(kāi)發(fā)特異性調(diào)節(jié)藥物具有重要的價(jià)值。補(bǔ)體是天然免疫系統(tǒng)的重要組分。研究表明,補(bǔ)體參與調(diào)節(jié)T細(xì)胞增殖分化。CD4+T細(xì)胞上表達(dá)補(bǔ)體受體C3a R及C5a R,與補(bǔ)體活化產(chǎn)物C3a及C5a結(jié)合后,激活G蛋白下游通路,促進(jìn)T細(xì)胞增殖分化及Th1細(xì)胞應(yīng)答。同種異基因小鼠腎移植中補(bǔ)體C5a R基因缺陷顯著延長(zhǎng)移植物存活,T細(xì)胞應(yīng)答明顯減弱,表明同種異基因移植排斥反應(yīng)中補(bǔ)體參與調(diào)節(jié)T細(xì)胞增殖分化。然而,同種異基因移植中補(bǔ)體活化是否與Th17細(xì)胞存在關(guān)聯(lián)并參與調(diào)節(jié)Th17細(xì)胞增殖分化尚不清楚。補(bǔ)體C3是補(bǔ)體系統(tǒng)的樞紐分子。補(bǔ)體C3基因缺陷時(shí),Th1/Th17細(xì)胞應(yīng)答衰減,同時(shí)補(bǔ)體C3參與調(diào)節(jié)Treg細(xì)胞增殖分化及功能發(fā)揮,提示同種異基因移植中補(bǔ)體C3可能參與調(diào)節(jié)Treg/Th17細(xì)胞應(yīng)答,在移植排斥反應(yīng)中發(fā)揮重要作用�！狙芯磕康摹�1、研究同種異基因移植過(guò)程中補(bǔ)體的活化及Th17細(xì)胞增殖分化的關(guān)聯(lián);2、建立同種異基因移植模型,明確補(bǔ)體組分C3對(duì)移植物存活及Th17細(xì)胞應(yīng)答的影響;3、深入探討補(bǔ)體C3對(duì)同種異基因移植排斥反應(yīng)中Th17細(xì)胞應(yīng)答的調(diào)控機(jī)制�！狙芯糠椒ā�1、同種異基因移植中補(bǔ)體的活化及Th17細(xì)胞的增殖分化1)收集腎移植患者外周血,分離PBMC及血清,FCM檢測(cè)移植排斥過(guò)程中Th17細(xì)胞增殖分化,ELISA檢測(cè)補(bǔ)體活化片段C3a及C5a含量,明確移植過(guò)程中補(bǔ)體活化情況;2)收集發(fā)生急慢性排斥反應(yīng)及正常腎組織,IHC檢測(cè)腎組織中補(bǔ)體活化、IL-17表達(dá)、T細(xì)胞浸潤(rùn),免疫熒光染色I(xiàn)F檢測(cè)排斥腎組織中Th17細(xì)胞浸潤(rùn)情況。3)培養(yǎng)人近端腎小管上皮細(xì)胞(HK2),以補(bǔ)體活化產(chǎn)物C3a刺激后,IHC檢測(cè)HK2中IL-17的分泌。4)補(bǔ)體活化產(chǎn)物C5a刺激HK2后,IHC及FCM檢測(cè)HK2中IL-17的分泌。2、同種異基因移植中補(bǔ)體組分C3對(duì)移植物存活及Th17細(xì)胞應(yīng)答的影響1)Bm12,C3+/+及C3-/-小鼠尾部皮膚分別移植到Bm12小鼠背部,7天后觀察移植物排斥反應(yīng),明確局部補(bǔ)體C3缺乏對(duì)同種異基因移植物存活的影響;2)Bm12小鼠尾部皮膚分別移植到C3+/+或者C3-/-小鼠背部,7天后觀察移植物排斥反應(yīng),明確系統(tǒng)性補(bǔ)體C3缺乏對(duì)同種異基因移植物存活的影響。3)通過(guò)HE、IHC及IF染色檢測(cè)移植物局部中性粒細(xì)胞、巨噬細(xì)胞、Th17細(xì)胞及DC等浸潤(rùn)情況,q PCR檢測(cè)移植物局部炎癥因子及趨化因子表達(dá)情況。4)移植不同時(shí)間點(diǎn),取Bm12小鼠腋窩引流淋巴結(jié)及脾臟,FCM檢測(cè)Th1/17細(xì)胞頻率,明確補(bǔ)體C3缺陷對(duì)Th1/17細(xì)胞應(yīng)答的影響。3、同種異基因移植中補(bǔ)體組分C3對(duì)Th17細(xì)胞應(yīng)答的調(diào)節(jié)機(jī)制1)移植10天后,取Bm12小鼠腋窩引流淋巴結(jié),MLR檢測(cè)補(bǔ)體C3缺陷對(duì)淋巴細(xì)胞增殖的影響。2)移植不同時(shí)間點(diǎn),取Bm12小鼠腋窩引流淋巴結(jié)及脾臟,FCM檢測(cè)Treg細(xì)胞頻率,明確在此模型中補(bǔ)體C3缺陷對(duì)Treg細(xì)胞應(yīng)答的影響。3)利用Anti-CD25 mAb去除Treg細(xì)胞后,觀察C3-/-移植物存活情況,深入探討Treg細(xì)胞在延長(zhǎng)C3-/-移植物存活中的重要作用。4)分離純化Na?ve CD4+T細(xì)胞與輻照后的BMDCs共培養(yǎng)9-12天,收集上清檢測(cè)IL-10的分泌,收集細(xì)胞通過(guò)PCR及FCM檢測(cè)Treg細(xì)胞增殖分化情況�！狙芯拷Y(jié)果】1、同種異基因移植中,補(bǔ)體大量活化及Th17細(xì)胞應(yīng)答增強(qiáng)1)與移植前相比,同種異基因腎移植后患者血清中補(bǔ)體活化片段C3a及C5a濃度顯著增加;發(fā)生排斥反應(yīng)腎組織中補(bǔ)體C3、補(bǔ)體受體C5a R及補(bǔ)體活化終產(chǎn)物C5b-9較正常腎組織表達(dá)明顯增加。2)與移植前相比,同種異基因腎移植后患者PBMCs中Th17細(xì)胞頻率升高;排斥反應(yīng)腎組織中Th17細(xì)胞浸潤(rùn)顯著增加。3)與未刺激組相比,補(bǔ)體活化產(chǎn)物C3a及C5a刺激顯著上調(diào)IL-17表達(dá)。2、局部補(bǔ)體組分C3缺陷顯著延長(zhǎng)同種異基因移植物存活時(shí)間并衰減Th17細(xì)胞應(yīng)答1)來(lái)源于C3+/+移植物在移植后17天被完全排斥,與之不同的是,來(lái)源于C3-/-移植物存活時(shí)間顯著延長(zhǎng),60%C3-/-B6移植物存活時(shí)間超過(guò)30天,表明移植物局部C3基因缺陷可延長(zhǎng)MHC-Ⅱ不匹配同種異基因移植物存活時(shí)間。2)Bm12移植物存活時(shí)間在C3+/+及C3-/-兩種小鼠間沒(méi)有差異,移植物存活時(shí)間均小于14天,表明系統(tǒng)性C3缺陷不能延長(zhǎng)同種異基因移植物存活時(shí)間。3)HE染色發(fā)現(xiàn),C3-/-移植物組織壞死、單核細(xì)胞浸潤(rùn)顯著減輕;IHC檢測(cè)發(fā)現(xiàn),C3-/-移植物中性粒細(xì)胞、巨噬細(xì)胞及T細(xì)胞浸潤(rùn)顯著減少;IF檢測(cè)發(fā)現(xiàn),C3-/-移植物局部Th17細(xì)胞浸潤(rùn)明顯減少。4)q PCR檢測(cè)發(fā)現(xiàn),C3-/-移植物中Th1/Th17細(xì)胞應(yīng)答關(guān)鍵炎癥因子,如細(xì)胞因子IFN-γ、IL-17及IL-23,趨化因子CXCL-9,mRNA表達(dá)顯著降低。與之相似的是炎癥因子IL-1β、IL-6及TNF-α在C3-/-移植物表達(dá)亦顯著衰減。表明,移植物局部補(bǔ)體C3缺乏導(dǎo)致Th1/Th17細(xì)胞應(yīng)答相關(guān)炎癥因子及趨化因子表達(dá)降低。5)FCM檢測(cè)發(fā)現(xiàn),C3-/-移植物顯著降低Th1/17細(xì)胞頻率,表明同種異基因移植中補(bǔ)體C3促進(jìn)Th1/17細(xì)胞應(yīng)答。3、同種異基因移植排斥中,補(bǔ)體組分C3抑制Treg細(xì)胞增殖分化,促進(jìn)Th17細(xì)胞應(yīng)答,加速排斥反應(yīng)發(fā)生1)MLR實(shí)驗(yàn)發(fā)現(xiàn),補(bǔ)體C3基因缺陷時(shí)淋巴細(xì)胞增殖顯著降低。2)PCR及IHC檢測(cè)移植物中Treg細(xì)胞特異性轉(zhuǎn)錄因子Foxp3表達(dá),發(fā)現(xiàn)C3-/-移植物中Foxp3表達(dá)顯著上升,表明C3-/-移植物存活延長(zhǎng)可能與Treg的密切相關(guān)。3)FCM檢測(cè)Bm12小鼠脾臟及引流淋巴結(jié)中Treg細(xì)胞頻率,發(fā)現(xiàn),C3-/-移植物顯著增加Treg細(xì)胞頻率,表明C3-/-移植物存活延長(zhǎng)可能依賴于Treg細(xì)胞的擴(kuò)增。4)Anti-CD25 m Ab去除Treg細(xì)胞后觀測(cè)C3-/-移植物存活,發(fā)現(xiàn),去除Treg細(xì)胞后Th17細(xì)胞應(yīng)答增強(qiáng),C3-/-移植物存活時(shí)間顯著縮短,排斥反應(yīng)明顯增強(qiáng),表明Treg在促進(jìn)C3-/-移植物存活延長(zhǎng)中發(fā)揮關(guān)鍵作用。5)IF檢測(cè)發(fā)現(xiàn),C3-/-移植物中DCs浸潤(rùn)明顯減少,共刺激分子CD80表達(dá)減弱;通過(guò)將BMDCs與Na?ve CD4+T細(xì)胞共培養(yǎng),發(fā)現(xiàn),與C3+/+DCs相比,C3-/-DCs能夠顯著促進(jìn)IL-10的分泌,Foxp3表達(dá)及Tregs增殖分化,表明補(bǔ)體C3通過(guò)DCs抑制Tregs細(xì)胞增殖分化。【主要結(jié)論】本研究中,我們通過(guò)收集臨床同種異基因腎移植標(biāo)本,檢測(cè)補(bǔ)體活化及Th17細(xì)胞增殖分化;通過(guò)體外細(xì)胞實(shí)驗(yàn),檢測(cè)補(bǔ)體活化產(chǎn)物對(duì)IL-17產(chǎn)生的影響;建立同種異基因移植模型,明確補(bǔ)體組分C3對(duì)移植物存活及Th17細(xì)胞應(yīng)答的影響;深入探討補(bǔ)體C3在同種異基因移植排斥中對(duì)Th17細(xì)胞應(yīng)答的調(diào)控機(jī)制,得出主要結(jié)論如下:1、同種異基因移植過(guò)程中,補(bǔ)體的大量活化與Th17細(xì)胞應(yīng)答緊密相關(guān);2、同種異基因移植中,補(bǔ)體C3缺陷顯著延長(zhǎng)移植物的存活時(shí)間并衰減Th17細(xì)胞應(yīng)答;3、同種異基因移植排斥反應(yīng)中,補(bǔ)體組分C3抑制Tregs細(xì)胞增殖分化,促進(jìn)Th17細(xì)胞應(yīng)答,加速排斥反應(yīng)發(fā)生。
[Abstract]:Transplantation is an effective treatment of organ failure, allograft rejection is a major cause of graft loss of.CD4+T cells is mediated rejection of transplanted cells, different subsets of CD4+T cells in allograft rejection in the different functions of.Th1 and Th17 cells accelerated allograft rejection, whereas Th2 and Treg cells inducing allograft tolerance the widely used immune suppressing drugs, such as cyclosporine A, FK506 and rapamycin, through inhibiting the proliferation and differentiation of T cell subsets in the regulation of transplant rejection, there are obvious limitations. Therefore, the development of new immunosuppressive agents selectively inhibit T cell subsets of anti rejection drugs is the future research direction of transplantation under the condition of T cell subsets differentiation regulation, to understand the pathophysiology of allograft rejection and development of selective intervention T cells anti rejection drugs with ten points To the meaning of.Th17 is important CD4+T cell subsets, mainly due to the secretion of IL-17 named.IL-17 to the site of inflammation to raise a lot of mononuclear cells, interaction of neutrophils and other inflammatory factors involved in the regulation of.Th17 cell immune inflammation in allergic asthma, diabetes, psoriasis, SLE and graft rejection is important effect of reaction. The study found that Th17 cells infiltration was significantly correlated with the severity of renal transplantation and renal tissue injury. Using specific antibodies blocking IL-17A lymphocytes and IFN- positive cell infiltration significantly reduced mice lung transplant, and relieve obstructive bronchitis. Transplantation research status of Th17 cell differentiation regulation mechanism, has the important value for the development of specific drug regulation. Complement is an important group of natural immune system. Research shows that the complement is involved in the regulation of T proliferation and differentiation in.CD cells The expression of C3a R and C5a R complement receptor on 4+T cells, binding and complement activation products of C3a and C5a after activation of G downstream pathway, promote the proliferation and differentiation of T cells and Th1 cell responses. Allogeneic mouse kidney transplantation R complement C5a gene defects significantly prolonged graft survival, T cell response was reduced, show that the same allogeneic transplantation rejection complement is involved in the regulation of proliferation and differentiation of T cells. However, allogeneic transplantation of Th17 cells and complement activation is associated and involved in the regulation of proliferation and differentiation of Th17 cells is not clear. C3 is the hub of the complement molecule of the complement system. Complement C3 gene defects, Th1/Th17 cell response attenuation, and complement C3 participation Treg regulates the differentiation and function of cell proliferation play, suggesting that allogeneic transplantation of complement C3 may be involved in the regulation of Treg/Th17 cell responses in allograft rejection and play an important role [research. The purpose of] 1, the complement of allogeneic transplantation and the activation of Th17 cell proliferation and differentiation related; 2, the establishment of allogeneic transplantation model, clear complement component C3 effect on graft survival and Th17 cell responses; 3, to further study the mechanism of regulation of complement C3 allogeneic transplantation rejection in Th17 cells in response. [Methods] 1 allogeneic transplantation of complement activation and proliferation and differentiation of Th17 cell 1) collected the peripheral blood of patients with renal transplantation, separation of PBMC and serum FCM detection, graft rejection in the process of proliferation and differentiation of Th17 cells, C3a and C5a in the detection of ELISA fragment of complement activation, clear the transplantation process in the case of complement activation; 2) were collected in acute and chronic rejection and normal renal tissue, complement activation, renal tissue to detect IHC IL-17 expression in T cells, immunofluorescence staining to detect IF rejection in renal tissue of Th17 cell infiltration .3) in cultured human proximal tubular epithelial cells (HK2), product of C3a stimulation to complement activation, secretion of.4 IL-17 IHC HK2) in the detection of complement activation product C5a after HK2 stimulation, IL-17 IHC and FCM HK2 detection in the secretion of.2, allogeneic transplantation in the C3 group complement effect on graft survival and Th17 cell response 1) Bm12, C3+/+ and C3-/- mice tail skin were transplanted into Bm12 mice, 7 days after the observation of graft rejection, clear local complement C3 deficiency plant survival effect on allogeneic; 2) Bm12 mice tail skin grafting respectively to C3+/+ or C3-/- mice after 7 days. Observation of graft rejection, a clear system of complement C3 deficiency on allogeneic allografts by HE.3), to detect local grafts of neutrophils, IHC and IF staining of macrophages, Th17 cells and DC infiltration, Q detection of PCR graft The expression of.4 local inflammatory cytokines and chemokines) transplantation at different time points, the Bm12 mice axillary draining lymph node and spleen, FCM detection of Th1/17 cell frequency, clear complement C3 defects affect Th1/17 cell responses to.3, allogeneic transplantation group complement C3 on Th17 cell response mechanisms regulating 1) transplantation 10 days later, Bm12 mice were sacrificed and axillary lymph node dissection, MLR detection of complement C3 defect effect on lymphocyte proliferation.2) transplantation at different time points, the Bm12 mice axillary draining lymph node and spleen, FCM detection of Treg cell frequency, clear complement C3 defects in this model of Treg cell responses to.3 cells by removal of Treg) Anti-CD25 mAb, C3-/- to observe the graft survival situation, in-depth study of Treg cells in the extended C3-/- shift.4 an important role in the survival of plants) separation and purification of Na? Ve and CD4+T cells after irradiation BMDCs were cultured for 9-12 days, collect Supernatant from detection of IL-10, PCR and FCM cells were collected by detection of Treg cell proliferation and differentiation. [results] 1, allogeneic transplantation, a large number of complement activation and Th17 cell response increased 1) compared with before transplantation, allogeneic renal transplantation serum complement activation fragment C3a and C5a were significantly the increase in renal tissue rejection; complement C3, activation of complement receptor C5a R and complement the end product C5b-9 compared with normal renal tissue was significantly increased compared with.2) before transplantation, allogeneic Th17 cell frequency after renal transplantation in patients with PBMCs increased; Th17 cells were significantly increased.3 rejection in renal tissue compared with) no stimulation group, complement activation products C3a and C5a stimulation significantly up-regulated the expression of IL-17.2, local complement component C3 defects significantly prolong the allograft survival time and attenuation of Th17 cell response 1) derived from C3+/+ Plants in 17 days after transplantation was completely excluded, and the difference is derived from the C3-/- graft survival time was significantly prolonged, 60%C3-/-B6 grafts survived more than 30 days, showed that the graft local C3 gene MHC- II does not match the defects can prolong the allograft survival time.2 Bm12) graft survival time in C3+/+ C3-/- and no differences between the two types of mice, the survival time of the grafts were less than 14 days, C3 shows that the system defects cannot prolong allograft survival time.3) HE staining showed that C3-/- graft tissue necrosis, infiltration of mononuclear cells significantly reduced; IHC assay showed that C3-/- graft neutrophils, macrophages and T cells were significantly decreased; IF assay showed that C3-/- graft local infiltration of Th17 cells significantly reduced.4) found Q PCR detection, C3-/- shift key inflammatory cytokines Th1/Th17 cell responses in plants, such as cytokines IFN-, IL-17 and IL-23, chemokine CXCL-9, mRNA expression was significantly reduced. Similar inflammatory cytokine of IL-1, IL-6 and TNF- alpha graft expression was also significantly attenuated in C3-/-. The graft showed that local complement C3 deficiency related inflammatory cytokines Th1/Th17 cell response and chemokine expression decreased FCM detection,.5) the C3-/- graft significantly reduced the frequency of Th1/17 cells, showed that allogeneic transplantation of complement C3 promotes Th1/17 cell responses to.3, allograft rejection, complement component C3 inhibited Treg cell proliferation and differentiation, promote Th17 cell response, accelerated rejection occurred in 1) MLR experiments found that complement C3 gene defects in lymphocyte proliferation significantly.2 PCR and IHC) to reduce the detection of Treg cells in grafts specific transcription factor Foxp3 expression, C3-/- graft Foxp3 expression was significantly increased, showed that C3-/- and Treg could prolong graft survival closely .3) FCM detection of Bm12 in mouse spleen and draining lymph nodes of Treg cell frequency, found that C3-/- graft significantly increased frequency of Treg cells, C3-/- showed that the graft survival may depend on the Treg cells was.4 Anti-CD25 m Ab) removal of Treg cells after observing C3-/- graft survival, found that the removal of Treg cells after Th17 cells increased response C3-/- graft survival time was significantly shortened, the rejection was significantly enhanced, showed that Treg in promoting C3-/- graft survival play a key role in the.5 extension) IF detection, C3-/- graft DCs infiltration was significantly reduced, the costimulatory molecule CD80 expression decreased by BMDCs and Na; ve? CD4+T cells were co cultured. Found that, compared with C3+/+DCs, C3-/-DCs can significantly promote the secretion of IL-10, Foxp3 and Tregs showed that the expression of proliferation and differentiation, complement C3 inhibits the proliferation and differentiation of Tregs cells by DCs. [] the main conclusions in this study, I Through the collection of clinical allogeneic renal transplantation specimens, detection of complement activation and proliferation and differentiation of Th17 cells; in vitro, affect the detection of complement activation products of IL-17; the establishment of allogeneic transplantation model, clear complement component C3 effect on graft survival and Th17 cell responses in the same study; complement C3 allogeneic transplantation rejection on Th17 cell response mechanism, main conclusions are as follows: 1, the process of allogeneic transplantation, complement activation is closely related with the immune response of Th17 cells; 2, allogeneic gene transplantation, complement C3 deficiency significantly prolong graft survival time and attenuation of Th17 cell response; 3 allogeneic transplantation, rejection, complement component C3 inhibited Tregs cell proliferation and differentiation, promote Th17 cell response, accelerated rejection.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R392.4

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