Pathways of allorecognition: implications for transplantation tolerance
Pathways of allorecognition: implications for transplantation tolerance
复制标题
DOI：
10.1016/s0966-3274(02)00055-2
复制
发表时间：
2002-08-01
影响因子：
1.5
通讯作者：
Lechler, RI
中科院分区：
文献类型：
--
作者：
Game, DS;Lechler, RI
当宿主免疫系统检测到同种非自身抗原时，发生同种异体识别，这是同种异体排斥反应的触发因素。宿主T细胞检测这些“外来”抗原，这些抗原大多来自基因组的高度多态性区域，称为主要组织相容性复合体。同种异体识别可以通过两种不同但不相互排斥的途径发生：直接和间接。直接途径由供体细胞表面上的完整的外来主要组织相容性分子的识别引起。当供体组织相容性分子被宿主抗原呈递细胞内化、加工和呈递为肽时，发生间接同种异体识别-这是免疫系统通常看到抗原的方式。然而，除了抗原识别之外，T细胞活化还需要提供共刺激信号，这是骨髓来源的特化抗原呈递细胞（APC）的特权。一旦这些细胞从移植器官中耗尽，如在移植的数周内发生的，移植物的实质细胞就不能驱动受体T细胞的直接途径活化。这些非专职APC上的同种异体抗原识别可能具有耐受效应，并且实际上，对直接途径反应的T细胞的频率随时间而减少，而不管是否发生慢性移植排斥。这意味着虽然直接途径在急性排斥反应中起主导作用，但不太可能导致慢性排斥反应。然而，T细胞反应的测定已经发现间接途径和慢性排斥反应之间的关联，并且动物模型支持间接途径在急性和慢性排斥反应中的作用。由于受体APC通过移植物的运输，间接途径可能永久活跃。这对追求临床耐受性提出的挑战是如何诱导具有间接同种特异性的T细胞耐受性。答案可能在于T细胞和APC之间相互作用的环境的操纵。除了没有共刺激的识别之外，还有其他情况下可以发生没有激活的识别，尽管体内相关性不确定。来自不同调节细胞的调节细胞因子或抑制性表面分子的存在，或作为负反馈环，可能会阻止激活;这也可能在没有足够刺激支持的情况下发生：最终结果可能由整体平衡决定。此外，一些肽可以充当T细胞活化的拮抗剂，通常当激动剂肽在结构上非常相似时。人们希望，这些机制的仔细研究将揭示方法，确保同种异体识别没有激活，从而供体特异性耐受。(C)2002 Elsevier Science B. V.保留所有权利。
Allorecognition occurs when the host immune system detects same-species, non-self antigens and this is the trigger for allograft rejection. Host T cells detect these 'foreign' antigens which are mostly derived from a highly polymorphic region of the genome called the major histocompatibility complex. Allorecognition can occur by two distinct, but not mutually exclusive pathways: direct and indirect. The direct pathway results from the recognition of foreign major histocompatibility molecules, intact, on the surface of donor cells. Indirect allorecognition occurs when donor histocompatibility molecules are internalised, processed, and presented as peptides by host antigen presenting cells-this is the manner in which the immune system normally sees antigen. However, in addition to antigen recognition, T cell activation requires the provision of costimulatory signals, the prerogative of bone marrow-derived, specialised antigen-presenting cells (APC). Once these have been depleted from a transplanted organ, as occurs within weeks of transplantation, the parenchymal cells of the transplant are incapable of driving direct pathway activation of recipient T cells. Alloantigen recognition on these non-professional APCs may have a tolerising effect and indeed, the frequency of T cells reactive to the direct pathway diminishes with time irrespective of whether or not chronic transplant rejection occurs. This implies that while the direct pathway plays a dominant role in acute rejection, it is unlikely to contribute to chronic rejection. Assays of T cell responses have, however, found an association between the indirect pathway and chronic rejection and animal models support a role for the indirect pathway in both acute and chronic rejection. The indirect pathway is likely to be permanently active due to traffic of recipient APCs through the graft. The challenge that this poses in the pursuit of clinical tolerance is how to induce tolerance in T cells with indirect allospecificity. The answer may lie in manipulation of the environment of the interaction between the T cell and APC. Apart from recognition without costimulation, there are other circumstances when recognition without activation can occur although the in vivo relevance is uncertain. The presence of regulatory cytokines or inhibitory surface molecules either from a distinct regulatory cell, or as a negative feedback loop may prevent activation; this could also happen without sufficient stimulatory support: the final outcome is likely to be decided by the overall balance. Furthermore, some peptides may act as antagonists to T cell activation, usually when the agonist peptide is structurally very similar. It is hoped that the careful study of these mechanisms will reveal ways of ensuring allorecognition without activation and thus donor-specific tolerance. (C) 2002 Elsevier Science B.V. All rights reserved.