發(fā)布時(shí)間：2018-03-02 13:02

  本文選題：移植物血管病　切入點(diǎn)：天然抗體　出處：《吉林大學(xué)》2017年博士論文　論文類型：學(xué)位論文

【摘要】：背景:T細(xì)胞靶向主流免疫抑制劑的應(yīng)用已大大改善了器官移植的早期預(yù)后,然而遠(yuǎn)期移植物存活率卻維持原樣。主要原因是不可避免的慢性排斥反應(yīng)。所有血管化實(shí)體移植器官最終都可能因?yàn)槁砸浦参镅懿《δ芩ソ�。以供體特異性抗體為主的抗體介導(dǎo)性排斥反應(yīng)通常被主流觀點(diǎn)認(rèn)為與移植物血管病有關(guān)。我們系列研究的早期研究結(jié)果發(fā)現(xiàn),雖然作為固有免疫系統(tǒng)的一部分,固有B細(xì)胞(小鼠的B1 B細(xì)胞)所分泌的天然抗體(Nab),獨(dú)立于供體特異性抗體以外,影響了腎移植物的遠(yuǎn)期預(yù)后。為了直接揭示移植物血管病與Nab的相互影響,我們選用小鼠主動脈移植模型來探索Nabs在慢性移植物血管病發(fā)病機(jī)制中的作用。材料與方法:1、誘導(dǎo)內(nèi)生性天然抗體:紫外線照射新鮮小鼠(C57BL/6)胸腺細(xì)胞懸液誘導(dǎo)凋亡后,尾靜脈注射給受體小鼠(C57BL/6),重復(fù)4次,每次間隔一周,流式細(xì)胞分析證實(shí)小鼠血清天然抗體含量是否隨之提高;2、建立小鼠主動脈移植模型:應(yīng)用“套管”技術(shù),用供體小鼠的胸主動脈置換受體小鼠的腎動脈下腹主動脈,用恰當(dāng)?shù)姆椒ㄔu估移植物血管病的嚴(yán)重程度;3、設(shè)立4個(gè)實(shí)驗(yàn)組分別為:(1)全錯(cuò)配(BALB/c→C57BL/6)/內(nèi)生性高Nab,(2)全錯(cuò)配/基線水平Nab,(3)無錯(cuò)配(C57BL/6→C57BL/6)/內(nèi)生性高Nab,(4)無錯(cuò)配/基線水平Nab。按照實(shí)驗(yàn)設(shè)計(jì)執(zhí)行手術(shù),術(shù)后6周獲取移植物做組織學(xué)分析。結(jié)果:1、流式細(xì)胞分析確認(rèn)小鼠血清Nab含量會隨著注射次數(shù)和時(shí)間的推移而增長,并且可以維持到實(shí)驗(yàn)終點(diǎn)(4-6周),內(nèi)生性Nab小鼠模型建立成功;2、“套管”法小鼠主動脈移植被證明是一種優(yōu)于傳統(tǒng)縫線血管吻合的手術(shù)方式,數(shù)字型變量內(nèi)膜增生指數(shù)(I/M)、血管狹窄度(%)和血管中膜單位面積細(xì)胞數(shù),可以準(zhǔn)確評價(jià)移植物血管病的嚴(yán)重程度;3、在內(nèi)生性Nab影響下的小鼠,接受異源(BALB/c→C57BL/6)主動脈移植后,移植物血管病的病程進(jìn)展相比全錯(cuò)配/未誘導(dǎo)Nab組小鼠有大幅延緩(全錯(cuò)配/Nab組:I/M=0.96±0.13,Occlusion%=24.8±3.9%;全錯(cuò)配/未誘導(dǎo)Nab組I/M=0.13±0.04,Occlusion%=4.4±2.0%;PI/M=0.004,Pocclusion=0.0108),內(nèi)膜完整度及管腔通暢程度幾乎與同源(無錯(cuò)配)移植對照組沒有區(qū)別(全錯(cuò)配/Nab組:I/M=0.13±0.04,Occlusion%=4.4±2.0%;無錯(cuò)配/未誘導(dǎo)Nab組:I/M=0.07±0.04,Occlusion%=5.8±0.2%;PI/M=0.3170,Pocclusion=0.6352)。結(jié)論:內(nèi)生性Nab的存在延緩了同種異體移植物血管管腔狹窄的進(jìn)程,同時(shí)沒有影響受體自身免疫系統(tǒng)的功能。
[Abstract]:Background the early prognosis of organ transplantation has been greatly improved by the use of major immunosuppressants targeting at: t cells. However, the long-term graft survival rate remains the same. The main reason is the inevitable chronic rejection. All vascularized solid transplant organs may eventually fail due to chronic graft angiopathy. Antibody-mediated rejection is commonly thought to be associated with graft angiopathy. Early findings in our series of studies have shown that. Although as part of the innate immune system, natural antibodies secreted by innate B cells (B 1 B cells in mice) are independent of donor-specific antibodies. In order to reveal the interaction between graft angiopathy and Nab, We selected mouse aortic transplantation model to explore the role of Nabs in the pathogenesis of chronic graft angiopathy. Materials and methods: 1, induced endogenous natural antibody: ultraviolet irradiation of fresh mouse C57BL / 6 thymocyte suspension induced apoptosis. Caudal vein was injected into the recipient mice C57BL / 6 and repeated four times, with a one-week interval. Flow cytometry confirmed whether the content of natural antibodies in the serum of mice was increased or not, and a mouse aortic transplantation model was established: the "cannula" technique was used. The abdominal aorta of the recipient mice was replaced by thoracic aorta of donor mice. The severity of graft angiopathy was evaluated by the appropriate method. 鈫扖57BL / 6 / endogenous high Nablite 2) Total mismatch / baseline level Nabo 3) no mismatch C57BL / 6. 鈫扤o mismatch / baseline Nab. according to the experimental design, the grafts were obtained 6 weeks after operation for histological analysis. Results: 1, flow cytometry confirmed that the serum Nab content of mice would increase with the number and time of injection. And it can be maintained until the experimental end point of 4-6 weeks, and the endogenous Nab mouse model was established successfully. The "cannula" method has been proved to be a better surgical method than traditional suture vascular anastomosis. The index of intimal hyperplasia (I / M) and the number of cells per unit area of vascular media can be used to accurately evaluate the severity of graft angiopathy in mice under the influence of endogenous Nab. 鈫扖57BL / 6) after aorta transplantation, The progression of grafts angiopathy was significantly delayed than that in the total mismatched / uninduced Nab group (total mismatch / nab group: 0.96 鹵0.13 Occlusion.24.8 鹵3.9T; I / M = 0.13 鹵0.04) in the Nab group, 4.4 鹵2.0PIP / M0.004Pocclusion 0.0108A, the degree of intimal integrity and patency of the lumen was almost homologous (no mismatch). There was no difference in control group (total mismatch / nab group: I / M 0.13 鹵0.04Occlusion = 4.4 鹵2.0; no mismatch / uninduced Nab group: I / M 0.07 鹵0.04Occlusion = 5.8 鹵0.2T = 0.3170Pocclusion 0.6352). Conclusion: the existence of endogenous Nab can delay the process of allograft vascular stenosis. At the same time, it does not affect the function of the receptor autoimmune system.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R543

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本文編號：1556628