空间距离在胸腺基质细胞培训胸腺细胞中的关键作用

发布时间：2018-03-31 05:11

本文选题：胸腺　切入点：异种移植　出处：《第三军医大学》2005年博士论文

【摘要】： 背景及目的:胸腺是培训胸腺细胞发育的首要场所,来源于骨髓的前T细胞进入胸腺环境中,从胸腺被膜下区,经胸腺皮质向皮质皮髓交界区、髓质移动,经一系列复杂的培训过程,包括增殖、受体基因重排、MHC限制的阳性选择、排除自身反应性和缺陷细胞的阴性选择、细胞表面分子和功能上的成熟等,确保了外周成熟T细胞可识别外源性抗原肽和自身MHC复合物(自身MHC限制性),并消除自身反应性T细胞(自身耐受)。这个过程中每一步都是在胸腺的微环境中进行,胸腺微环境主要由胸腺基质细胞和细胞外基质组成,其中胸腺基质细胞是胸腺微环境中最重要的成分。胸腺基质细胞在胸腺中以三维立体构成网状支架结构,胸腺细胞与基质细胞在不同区域的相互作用对精密有序地完成了阳性选择和阴性选择起重要的作用。胸腺基质细胞在空间、时间上为胸腺细胞的培训提供了最适合的微环境,对胸腺细胞分化以及功能性亚群的形成有决定性的作用。胸腺不仅在建立和塑造有功能的T细胞库中发挥作用,而且对诱导和维持自身耐受和移植耐受起关键作用。经胸腺途径诱导免疫耐受已进行了广泛研究,主要的机理是通过胸腺的选择作用,消除自身、同种、异种供体反应性T细胞,从而达到较稳定的免疫耐受。最近发现在胸腺基质细胞广泛地表达外周组织器官的组织特异性抗原,所以胸腺基质细胞被认为是外周组织器官的自身抗原库的镜子,在自身耐受和维持免疫自身稳定起着关键性作用。异种胸腺移植不仅可以重建有功能的细胞免疫功能,而且可以诱导供者特异性免疫耐受,但其面临的主要问题是宿主T细胞在异种胸腺内成熟后不能产生对宿主抗原足够的自身耐受,而发生了多器官的自身免疫损害,如甲状腺炎、泪腺炎、卵巢炎以及胃炎等,而同系或同种胸腺移植的受者未发生自身免疫综合征。我们以前将同系胸腺与异种胸腺充分混合后再进行移植,既能诱导供体特异性的免疫耐受,又能防止自身免疫损害的发生。然而胸腺细胞在混合胸腺中是如何被训练的并不清楚;也不知道从骨髓来源的前T细胞进入混合胸腺后,是一个克隆的T细胞经历混合胸腺中的一个胸腺培训,还是要经历两个不同胸腺的共同培训?因此我们设计了将不同种类的两种胸腺分别移植在一个机体内的不同部位,并进行T细胞示踪
[Abstract]:Background and objective: the thymus is the primary place for training thymocytes to develop. The former T cells from bone marrow enter the thymus environment and move from the thymic submembrane region, the thymic cortex to the cortical medullary junction region, and the medulla. After a series of complex training processes, including proliferation, receptor gene rearrangement, MHC restricted positive selection, exclusion of self-reactivity and negative selection of defective cells, cell surface molecular and functional maturation, etc. It ensures that peripheral mature T cells can recognize exogenous antigenic peptides and their own MHC complexes (self MHC restricted T cells) and eliminate autoreactive T cells (autotolerance). Each step of this process takes place in the microenvironment of the thymus. Thymic microenvironment is mainly composed of thymic stromal cells and extracellular matrix, among which thymic stromal cells are the most important components in thymus microenvironment. The interaction between thymocytes and stromal cells in different regions plays an important role in the precise and orderly completion of positive and negative selection. Thymic stromal cells provide the most suitable microenvironment for the training of thymocytes in space and time. It plays a decisive role in the differentiation of thymocytes and the formation of functional subsets. Thymus not only plays a role in the establishment and formation of functional T cell banks, but also plays a key role in inducing and maintaining self-tolerance and transplantation tolerance. The induction of immune tolerance through thymus pathway has been extensively studied. The main mechanism is to eliminate self, allogeneic and xenogeneic donor reactive T cells through thymus selection. It has recently been found that thymic stromal cells widely express tissue-specific antigens in peripheral tissues and organs, so thymic stromal cells are considered to be a mirror of the antigen-library of peripheral tissues and organs. Xenogeneic thymus transplantation can not only reconstruct the functional cellular immune function, but also induce donor specific immune tolerance. However, the main problem it faces is that the host T cells cannot produce sufficient tolerance to host antigens after maturation in the xenogeneic thymus, and autoimmune damage occurs in many organs, such as thyroiditis, lacrimal gland inflammation, ovary inflammation and gastritis, etc. But the recipient of homologous or allogeneic thymus transplantation did not develop autoimmune syndrome. We used to mix homologous thymus with heterologous thymus before transplantation, which can induce donor-specific immune tolerance. But it's not clear how the thymocytes are trained in the mixed thymus, or how they get into the mixed thymus from pre-T cells from bone marrow. Is a cloned T cell trained in a single thymus in a mixed thymus, or is it a common training for two different thymus? So we designed to transplant two different kinds of thymus into different parts of the body and do T cell tracing.
【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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