本文關鍵詞：體外共刺激阻斷模型中耐受T細胞對NK細胞功能的調(diào)節(jié)作用及其機制初探　出處：《第三軍醫(yī)大學》2005年博士論文　論文類型：學位論文

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【摘要】：T 淋巴細胞是機體細胞免疫的重要執(zhí)行和調(diào)節(jié)細胞。在組織器官移植細胞性免疫排斥反應研究中,T細胞是最重要的研究對象。但研究表明,清除或抑制T 細胞并不能誘導終生耐受,而種種跡象表明NK 細胞在移植排斥反應中占有非常重要的地位,若在器官移植前用抗NK1.1 單抗去除NK 細胞,可顯著延長異種移植物的存活時間。顯然,單純誘導T 細胞耐受不足以完全克服移植排斥反應,要誘導較長期甚至終生的免疫耐受還應考慮其它參與排斥反應的因素,如Mf 、NK 細胞等。作為天然免疫的重要組成,NK 細胞是最早出現(xiàn)在移植局部的細胞之一,也是特異性細胞免疫的重要效應細胞,NK 細胞的功能狀態(tài)與器官移植的預后密切相關。作為免疫應答的主要細胞之一,NK 細胞既參與應答的調(diào)節(jié),其功能亦受多種因素的影響。 本實驗室在國家自然科學基金面上項目(30200261)資助下,在將同系小鼠胎胸腺與異種大鼠(F344)胎胸腺混合后移植給Balb/c 裸小鼠,成功的建立了異種耐受模型。研究中發(fā)現(xiàn)在Balb/c 裸小鼠上進行異種皮膚移植(F344? nude mice), 20 天左右即被排斥,而在事先接受混合胸腺移植的裸鼠上進行同樣的實驗則發(fā)現(xiàn)異種移植物存活時間顯著延長。顯然,在胸腺缺陷的裸鼠,存在非胸腺依賴方式,如NK 細胞等排斥移植物,而這些途徑則可能被供體耐受的T 細胞所抑制。有文獻提示,在胸腺移植耐受模型及阻斷CD28/B7 共刺激通路誘導的移植耐受動物模型中,NK 細胞的細胞毒性作用將在相當一段時間內(nèi)受到抑制。那么,NK 細胞的免疫抑制與T 細胞的耐受之間到底有何聯(lián)系?其內(nèi)在機制又是什么呢? 免疫排斥反應是一十分復雜的事件,在這一事件中除居于主導地位的T 淋巴細胞外,NK 細胞也起著非常重要的的作用。文獻及前文所述模型均提示我們,耐受的T細胞可能抑制或干預NK 細胞的作用,為此,我們確定NK 細胞作為研究對象,用抗CD80 抗體阻斷CD28/B7 信號通路建立體外近交系小鼠T 細胞耐受模型,并通過該模型研究耐受T細胞對NK 細胞功能可能的調(diào)控作用及其機制,包括影響NK 細胞功能的主要T 細胞亞群、APC 細胞的影響及可能的分子機制等。這不僅有利于進一步
[Abstract]:T lymphocyte is an important cellular immune and regulate cells in organ transplantation. Cellular immune rejection of T cells is the most important research object. But research shows that removal or inhibition of T cells did not induce lifetime tolerance, and signs that the NK cells in the graft rejection reaction occupies a very important position if, before organ transplantation with anti NK1.1 monoclonal antibody to remove NK cells can significantly prolong xenograft survival time. Obviously, the simple induction of T cell tolerance is not enough to completely overcome graft rejection, to induce long-term or even lifelong immune tolerance should also consider other factors, involved in the rejection of such as Mf, NK cells. As an important component of innate immunity, NK cells are first appeared in one of the local cell transplantation, and is also an important effect cell specific cellular immunity, NK cell function The status is closely related to the prognosis of organ transplantation. As one of the main cells of immune response, NK cells are involved in the regulation of responses, and their functions are also influenced by many factors.
The laboratory in the National Natural Science Foundation of China (30200261) under the auspices of the mice with thymus from fetal rat fetal thymus (F344) hybrid were transplanted into Balb/c nude mice, the successful establishment of heterogenous tolerance model. Study found that xenogeneic skin transplantation in Balb/c nude mice (nude mice on F344?), 20 days or so will be rejected, and the same experiments were carried out in advance to accept mixed thymus transplantation in nude mice found that xenografts survival time was significantly prolonged. Obviously, the existence of defects in the thymus in nude mice, thymus dependent manner, such as NK cells, graft rejection, and inhibition of these pathways may be donor tolerance of T cells. There are hints in the literature, in the thymus transplantation tolerance model and blockade of CD28/B7 costimulatory pathway induced animal model of transplantation tolerance, the cytotoxicity of NK cells will be in a period of time Suppressing. Then, what is the connection between the immunosuppression of NK cells and the tolerance of T cells? What is the intrinsic mechanism of it?
Immune rejection is a very complicated event, during the event in addition to the dominant T lymphocytes, NK cells also play a very important role. The previous models showed us tolerance of T cells could inhibit or interfere NK cells. Therefore, we identified NK cells as the research object, the CD28/B7 signaling pathway in vitro inbred tolerance of mice model of T cells with anti CD80 antibody blocking, and its mechanisms and the model of tolerance of T cells to NK cells may function, including the main function of the T cell NK cell subsets, APC cells and the possible molecular mechanism this is not only conducive to further.

【學位授予單位】：第三軍醫(yī)大學
【學位級別】：博士
【學位授予年份】：2005
【分類號】：R392

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