Brigham and Women's Hospital, Transplantation Research Center, Harvard Medical School, Renal Division , Boston, MA , USA +1 617 525 8005 ; +1 617 732 5254 ;
Expert Opin Ther Targets. 2014 Feb;18(2):225-42. doi: 10.1517/14728222.2014.863875. Epub 2013 Dec 12.
The pivotal role of costimulatory pathways in regulating T-cell activation versus tolerance has stimulated tremendous interest in their manipulation for therapeutic purposes. Of these, the CD28-B7 pathway is arguably the most important and best studied. Therapeutic targets of CD28 are currently used in the treatment of melanoma, autoimmune diseases and in transplantation.
In this review, we summarize our current knowledge of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) signaling, and review the current state and challenges of harnessing them to promote transplant tolerance.
Despite the success of belatacept, a first-in-class CTLA-4 fusion protein now clinically used in transplantation, it is apparent that we have only scratched the surface in understanding the complexities of how costimulatory pathways modulate the immune system. Our initial assumption that positive costimulators activate effector T cells and prevent tolerance, while negative costimulators inhibit effector T cells and promote tolerance, is clearly an oversimplified view. Indeed, belatacept is not only capable of blocking deleterious CD28-B7 interactions that promote effector T-cell responses but can also have undesired effects on tolerogenic regulatory T-cell populations.
共刺激途径在调节 T 细胞激活与耐受中的关键作用激发了人们对其进行治疗性操纵的极大兴趣。在这些途径中，CD28-B7 途径可以说是最重要和研究最多的。目前，CD28 的治疗靶点用于治疗黑色素瘤、自身免疫性疾病和移植。
在这篇综述中，我们总结了我们目前对 CD28 和细胞毒性 T 淋巴细胞抗原 4（CTLA-4）信号的了解，并回顾了利用它们促进移植耐受的现状和挑战。
尽管 CTLA-4 融合蛋白贝那西普作为一种首创的 CTLA-4 融合蛋白在移植中已被临床应用，但显然我们在理解共刺激途径如何调节免疫系统的复杂性方面只是略知一二。我们最初的假设是，正共刺激物激活效应 T 细胞并防止耐受，而负共刺激物抑制效应 T 细胞并促进耐受，这显然是过于简单的观点。事实上，贝那西普不仅能够阻断促进效应 T 细胞反应的有害 CD28-B7 相互作用，而且对诱导耐受的调节性 T 细胞群体也可能产生不良影响。
