本文選題：胸腺　切入點：異種移植　出處：《第三軍醫(yī)大學》2005年博士論文

【摘要】： 背景及目的:胸腺是培訓胸腺細胞發(fā)育的首要場所,來源于骨髓的前T細胞進入胸腺環(huán)境中,從胸腺被膜下區(qū),經胸腺皮質向皮質皮髓交界區(qū)、髓質移動,經一系列復雜的培訓過程,包括增殖、受體基因重排、MHC限制的陽性選擇、排除自身反應性和缺陷細胞的陰性選擇、細胞表面分子和功能上的成熟等,確保了外周成熟T細胞可識別外源性抗原肽和自身MHC復合物(自身MHC限制性),并消除自身反應性T細胞(自身耐受)。這個過程中每一步都是在胸腺的微環(huán)境中進行,胸腺微環(huán)境主要由胸腺基質細胞和細胞外基質組成,其中胸腺基質細胞是胸腺微環(huán)境中最重要的成分。胸腺基質細胞在胸腺中以三維立體構成網狀支架結構,胸腺細胞與基質細胞在不同區(qū)域的相互作用對精密有序地完成了陽性選擇和陰性選擇起重要的作用。胸腺基質細胞在空間、時間上為胸腺細胞的培訓提供了最適合的微環(huán)境,對胸腺細胞分化以及功能性亞群的形成有決定性的作用。 胸腺不僅在建立和塑造有功能的T細胞庫中發(fā)揮作用,而且對誘導和維持自身耐受和移植耐受起關鍵作用。經胸腺途徑誘導免疫耐受已進行了廣泛研究,主要的機理是通過胸腺的選擇作用,消除自身、同種、異種供體反應性T細胞,從而達到較穩(wěn)定的免疫耐受。最近發(fā)現(xiàn)在胸腺基質細胞廣泛地表達外周組織器官的組織特異性抗原,所以胸腺基質細胞被認為是外周組織器官的自身抗原庫的鏡子,在自身耐受和維持免疫自身穩(wěn)定起著關鍵性作用。異種胸腺移植不僅可以重建有功能的細胞免疫功能,而且可以誘導供者特異性免疫耐受,但其面臨的主要問題是宿主T細胞在異種胸腺內成熟后不能產生對宿主抗原足夠的自身耐受,而發(fā)生了多器官的自身免疫損害,如甲狀腺炎、淚腺炎、卵巢炎以及胃炎等,而同系或同種胸腺移植的受者未發(fā)生自身免疫綜合征。我們以前將同系胸腺與異種胸腺充分混合后再進行移植,既能誘導供體特異性的免疫耐受,又能防止自身免疫損害的發(fā)生。然而胸腺細胞在混合胸腺中是如何被訓練的并不清楚;也不知道從骨髓來源的前T細胞進入混合胸腺后,是一個克隆的T細胞經歷混合胸腺中的一個胸腺培訓,還是要經歷兩個不同胸腺的共同培訓?因此我們設計了將不同種類的兩種胸腺分別移植在一個機體內的不同部位,并進行T細胞示蹤
[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.
【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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本文編號：1689282