Transplantation Research Center, Brigham and Woman's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Curr Opin Organ Transplant. 2008 Aug;13(4):373-8. doi: 10.1097/MOT.0b013e328306117f.
Negative T-cell costimulatory pathways regulate T-cell responses and are of great interest in the development of tolerance-inducing strategies in transplantation. This article provides an update of major contributions to the understanding of the known negative costimulatory pathways, and reviews recent studies on the effects of targeting of these pathways in alloimmunity.
Graft tissue expression of negative costimulatory molecules, especially programmed death receptor ligand 1, plays a major role in regulation of alloimmune responses. The recently demonstrated programmed death receptor ligand 1:B7-1 interaction highlights the complexity and possible redundancy/hierarchy of the functions of these pathways in vivo. CD160 was identified as a ligand of Herpes virus entry mediator and has been established as a new coinhibitory molecule. A soluble form of B7-H3 with possible functional roles has been identified in mice and humans.
The understanding of negative costimulatory pathways is embarrassed by complex interactions between simultaneously activated positive and negative costimulatory pathways among themselves and with immunosuppressive agents, differential expression of these molecules on different immune cell subsets as well as their expression in parenchymal cells of transplanted tissues, all of them clearly affecting their functions. Further elucidation of these novel concepts is pertinent for targeting these pathways in translational studies in near future.
目的综述：负性 T 细胞共刺激通路可调节 T 细胞反应，在移植中诱导耐受的策略发展中具有重要意义。本文就目前已知的负性共刺激通路的理解提供了主要进展，并对这些通路在同种异体免疫中的靶向作用的最新研究进行了综述。
最新发现：移植组织中负性共刺激分子（尤其是程序性死亡受体配体 1）的表达在调节同种免疫反应中起着主要作用。新近发现的程序性死亡受体配体 1：B7-1 相互作用突出了这些通路在体内的功能的复杂性和可能的冗余/层次。CD160 被鉴定为疱疹病毒进入介体的配体，并已被确立为一种新的共抑制分子。在小鼠和人类中发现了具有潜在功能的 B7-H3 的可溶性形式。
总结：由于阳性和负性共刺激通路之间以及与免疫抑制剂之间的复杂相互作用、这些分子在不同免疫细胞亚群上的差异表达以及它们在移植组织实质细胞中的表达，负性共刺激通路的理解受到了阻碍，所有这些都明显影响了它们的功能。进一步阐明这些新的概念对于未来在转化研究中靶向这些通路具有重要意义。
