Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon, Leon, Spain; Leon University Hospital, Castilla and Leon Transplantation Regional Agency, Leon, Spain.
Xenotransplantation. 2013 Nov-Dec;20(6):397-406. doi: 10.1111/xen.12049. Epub 2013 Aug 22.
Xenotransplantation is an innovative field of research with the potential to provide us with an alternative source of organs to face the severe shortage of human organ donors. For several reasons, pigs have been chosen as the most suitable source of organs and tissues for transplantation in humans. However, porcine xenografts undergo cellular immune responses representing a major barrier to their acceptance and normal functioning. Innate and adaptive xenogeneic immunity is mediated by both the recognition of xenogeneic tissue antigens and the lack of inhibition due to molecular cross-species incompatibilities of regulatory pathways. Therefore, the delivery of immunoreceptor tyrosine-based inhibitory motif (ITIM)-dependent and related negative signals to control innate (NK cells, macrophages) and adaptive T and B cells might overcome cell-mediated xenogeneic immunity. The proof of this concept has already been achieved in vitro by the transgenic overexpression of human ligands of several inhibitory receptors in porcine cells resulting in their resistance against xenoreactivity. Consequently, several transgenic pigs expressing tissue-specific human ligands of inhibitory coreceptors (HLA-E, CD47) or soluble competitors of costimulation (belatacept) have already been generated. The development of these robust and innovative approaches to modulate human anti-pig cellular immune responses, complementary to conventional immunosuppression, will help to achieve long-term xenograft survival. In this review, we will focus on the current strategies to enhance negative signaling pathways for the regulation of undesirable cell-mediated xenoreactive immune responses.
异种移植是一个具有创新性的研究领域，有潜力为我们提供一种替代来源的器官，以解决人类器官捐献者严重短缺的问题。出于多种原因，猪已被选为最适合用于人类移植的器官和组织来源。然而，猪的异种移植物会引发细胞免疫反应，这是它们被接受和正常功能的主要障碍。先天和适应性的异种免疫是由对异种组织抗原的识别以及由于调节途径的分子跨物种不兼容性而缺乏抑制作用介导的。因此，传递免疫受体酪氨酸基抑制基序 (ITIM) 依赖性和相关的负信号来控制先天 (NK 细胞、巨噬细胞) 和适应性 T 和 B 细胞，可能克服细胞介导的异种免疫。通过在猪细胞中转基因过表达几种抑制性受体的人类配体，已经在体外证明了这一概念，从而使它们对异种反应具有抗性。因此，已经产生了几种表达组织特异性人类抑制性共受体配体（HLA-E、CD47）或共刺激可溶性竞争物（贝利昔单抗）的转基因猪。这些强大和创新的方法的发展，有助于调节人类抗猪细胞免疫反应，与传统免疫抑制相辅相成，将有助于实现长期的异种移植物存活。在这篇综述中，我们将重点介绍增强负信号通路以调节不期望的细胞介导异种免疫反应的当前策略。
