Murakami Naoka, Riella Leonardo V
1 Department of Medicine, Beth Israel Medical Center, New York, NY. 2 Transplantation Research Center, Renal Division, Brigham & Women's Hospital, Boston Children's Hospital, Harvard Medical School, Boston, MA. 3 Address correspondence to: Leonardo V. Riella, M.D., Ph.D., Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston MA 02115.
Transplantation. 2014 Jul 15;98(1):3-14. doi: 10.1097/TP.0000000000000169.
Immune regulation is critical for the maintenance of peripheral self-tolerance and for down-regulation of immune responses. Understanding its mechanisms may permit the development of novel targets for the promotion of tolerance in transplantation. Co-inhibitory molecules play a major role in modulating T-cell receptor signaling upon antigen encounter. Their unique patterns of expression, structure, and binding partners account for their diverse function and non-redundancy. Moreover, these inhibitory signals have active roles in both effector and regulatory immune cells in multiple sites, including the target tissue. Herein, we review the recent advances in our understanding of co-inhibitory signaling and its potential clinical applications, focusing mainly on the two best-characterized receptors CTLA4 and PD-1. Recent observations in cancer clinical trials using blocking antibodies against PD-1 or CTLA4, or both, showed a high incidence of autoimmune-related side effects, confirming the important role of these pathways in human immune homeostasis.
免疫调节对于维持外周自身耐受性和下调免疫反应至关重要。了解其机制可能有助于开发促进移植耐受的新靶点。共抑制分子在抗原接触时调节T细胞受体信号传导中起主要作用。它们独特的表达模式、结构和结合伙伴决定了它们的多样功能和非冗余性。此外，这些抑制信号在包括靶组织在内的多个部位的效应免疫细胞和调节性免疫细胞中均发挥积极作用。在此，我们综述了对共抑制信号及其潜在临床应用的最新认识进展，主要聚焦于两个特征最明确的受体CTLA4和PD-1。近期在癌症临床试验中使用抗PD-1或CTLA4或两者的阻断抗体的观察结果显示，自身免疫相关副作用的发生率很高，证实了这些通路在人类免疫稳态中的重要作用。
