体外共刺激阻断模型中耐受T细胞对NK细胞功能的调节作用及其机制初探

发布时间：2018-01-04 01:26

本文关键词：体外共刺激阻断模型中耐受T细胞对NK细胞功能的调节作用及其机制初探　出处：《第三军医大学》2005年博士论文　论文类型：学位论文

【摘要】：T 淋巴细胞是机体细胞免疫的重要执行和调节细胞。在组织器官移植细胞性免疫排斥反应研究中,T细胞是最重要的研究对象。但研究表明,清除或抑制T 细胞并不能诱导终生耐受,而种种迹象表明NK 细胞在移植排斥反应中占有非常重要的地位,若在器官移植前用抗NK1.1 单抗去除NK 细胞,可显著延长异种移植物的存活时间。显然,单纯诱导T 细胞耐受不足以完全克服移植排斥反应,要诱导较长期甚至终生的免疫耐受还应考虑其它参与排斥反应的因素,如Mf 、NK 细胞等。作为天然免疫的重要组成,NK 细胞是最早出现在移植局部的细胞之一,也是特异性细胞免疫的重要效应细胞,NK 细胞的功能状态与器官移植的预后密切相关。作为免疫应答的主要细胞之一,NK 细胞既参与应答的调节,其功能亦受多种因素的影响。本实验室在国家自然科学基金面上项目(30200261)资助下,在将同系小鼠胎胸腺与异种大鼠(F344)胎胸腺混合后移植给Balb/c 裸小鼠,成功的建立了异种耐受模型。研究中发现在Balb/c 裸小鼠上进行异种皮肤移植(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进行同样的实验则发现异种移植物存活时间显著延长。显然,在胸腺缺陷的裸鼠,存在非胸腺依赖方式,如NK 细胞等排斥移植物,而这些途径则可能被供体耐受的T 细胞所抑制。有文献提示,在胸腺移植耐受模型及阻断CD28/B7 共刺激通路诱导的移植耐受动物模型中,NK 细胞的细胞毒性作用将在相当一段时间内受到抑制。那么,NK 细胞的免疫抑制与T 细胞的耐受之间到底有何联系?其内在机制又是什么呢? 免疫排斥反应是一十分复杂的事件,在这一事件中除居于主导地位的T 淋巴细胞外,NK 细胞也起着非常重要的的作用。文献及前文所述模型均提示我们,耐受的T细胞可能抑制或干预NK 细胞的作用,为此,我们确定NK 细胞作为研究对象,用抗CD80 抗体阻断CD28/B7 信号通路建立体外近交系小鼠T 细胞耐受模型,并通过该模型研究耐受T细胞对NK 细胞功能可能的调控作用及其机制,包括影响NK 细胞功能的主要T 细胞亚群、APC 细胞的影响及可能的分子机制等。这不仅有利于进一步
[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.

【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R392

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