MacDonald Kelli Pa, Blazar Bruce R, Hill Geoffrey R
Antigen Presentation and Immunoregulation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Masonic Cancer Center; and Division of Blood and Marrow Transplantation, Department of Pediatrics; University of Minnesota, Minneapolis, USA.
J Clin Invest. 2017 Jun 30;127(7):2452-2463. doi: 10.1172/JCI90593.
Substantial preclinical and clinical research into chronic graft-versus-host disease (cGVHD) has come to fruition in the last five years, generating a clear understanding of a complex cytokine-driven cellular network. cGVHD is mediated by naive T cells differentiating within IL-17-secreting T cell and follicular Th cell paradigms to generate IL-21 and IL-17A, which drive pathogenic germinal center (GC) B cell reactions and monocyte-macrophage differentiation, respectively. cGVHD pathogenesis includes thymic damage, impaired antigen presentation, and a failure in IL-2-dependent Treg homeostasis. Pathogenic GC B cell and macrophage reactions culminate in antibody formation and TGF-β secretion, respectively, leading to fibrosis. This new understanding permits the design of rational cytokine and intracellular signaling pathway-targeted therapeutics, reviewed herein.
在过去五年中，针对慢性移植物抗宿主病（cGVHD）的大量临床前和临床研究取得了成果，对一个复杂的细胞因子驱动的细胞网络有了清晰的认识。cGVHD是由幼稚T细胞在分泌IL-17的T细胞和滤泡辅助性T细胞模式中分化介导的，分别产生IL-21和IL-17A，它们分别驱动致病性生发中心（GC）B细胞反应和单核细胞-巨噬细胞分化。cGVHD发病机制包括胸腺损伤、抗原呈递受损以及IL-2依赖的调节性T细胞稳态失衡。致病性GC B细胞和巨噬细胞反应分别最终导致抗体形成和TGF-β分泌，从而导致纤维化。这种新认识使得设计合理的细胞因子和细胞内信号通路靶向疗法成为可能，本文对此进行了综述。
