Game David S, Lechler Robert I
Department of Immunology, Imperial College School of Medicine, London, UK.
Transpl Immunol. 2002 Aug;10(2-3):101-8. doi: 10.1016/s0966-3274(02)00055-2.
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.
当宿主免疫系统检测到同物种的非自身抗原时，就会发生同种异体识别，这是同种异体移植排斥反应的触发因素。宿主T细胞检测到这些“外来”抗原，它们大多来自基因组中一个高度多态性的区域，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并非相互排斥的途径发生：直接途径和间接途径。直接途径是由于识别供体细胞表面完整的外来主要组织相容性分子而产生的。当供体组织相容性分子被宿主抗原呈递细胞内化、加工并呈递为肽时，就会发生间接同种异体识别——这是免疫系统通常识别抗原的方式。然而，除了抗原识别外，T细胞活化还需要提供共刺激信号，这是骨髓来源的专门抗原呈递细胞（APC）的特权。一旦这些细胞从移植器官中耗尽，就像移植后几周内发生的那样，移植的实质细胞就无法驱动受体T细胞的直接途径活化。在这些非专职APC上的同种异体抗原识别可能具有耐受作用，实际上，无论是否发生慢性移植排斥反应，对直接途径有反应的T细胞频率都会随着时间的推移而降低。这意味着虽然直接途径在急性排斥反应中起主导作用，但它不太可能导致慢性排斥反应。然而，T细胞反应的检测发现间接途径与慢性排斥反应之间存在关联，动物模型也支持间接途径在急性和慢性排斥反应中都起作用。由于受体APC通过移植物的运输，间接途径可能会永久活跃。在追求临床耐受方面，这带来的挑战是如何诱导对间接同种异体特异性的T细胞产生耐受。答案可能在于操纵T细胞与APC之间相互作用的环境。除了无共刺激的识别外，在其他情况下也可能发生无活化的识别，尽管其体内相关性尚不确定。来自不同调节细胞的调节性细胞因子或抑制性表面分子的存在，或者作为负反馈回路，可能会阻止活化；在没有足够刺激支持的情况下也可能发生这种情况：最终结果可能由整体平衡决定。此外，一些肽可能作为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。希望对这些机制的仔细研究将揭示确保无活化的同种异体识别从而实现供体特异性耐受的方法。
