Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510080, P. R. China.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, P. R. China.
Sci Rep. 2017 Jun 15;7(1):3603. doi: 10.1038/s41598-017-03700-1.
C5aR signaling plays an important role in the regulation of T cell activation and alloimmune responses in chronic graft-versus-host disease (cGVHD). However, direct evidence of this modulation and the efficacy of C5aR blockade in the treatment of cGVHD have not been demonstrated. We observed higher expression of C5aR on both monocytes and T cells of patients with cGVHD compared with healthy controls and non-GVHD patients after allogeneic hematopoietic stem cell transplantation. Our data also demonstrated a significant negative correlation between C5aR expression and regulatory T cells (Treg) frequency in cGVHD patients, indicating a potential role of C5aR in the generation and regulation of Treg. In addition, an in vitro experiment revealed C5aR deficiency promoted the development of Treg whereas C5a activation abolished the differentiation of Treg. Importantly, we found C5aR blockade by PMX53 attenuated the pathology of cGVHD and improved the survival of cGVHD mice. PMX53 had a direct regulatory effect on Treg commitment and increased TGF-β1 expression. Thus, C5aR signaling may induce and intensify cGVHD by down-regulating Treg induction. The modulation of C5aR activation by PMX53 may provide a potential therapy for cGVHD.
C5aR 信号在慢性移植物抗宿主病（cGVHD）中调节 T 细胞激活和同种免疫反应中发挥重要作用。然而，尚未证明这种调节的直接证据以及 C5aR 阻断在 cGVHD 治疗中的疗效。我们观察到，与健康对照者和异基因造血干细胞移植后的非 GVHD 患者相比，cGVHD 患者的单核细胞和 T 细胞上 C5aR 的表达更高。我们的数据还表明，cGVHD 患者 C5aR 表达与调节性 T 细胞（Treg）频率之间存在显著的负相关，表明 C5aR 在 Treg 的产生和调节中可能发挥作用。此外，体外实验表明 C5aR 缺乏促进了 Treg 的发展，而 C5a 的激活则消除了 Treg 的分化。重要的是，我们发现 PMX53 阻断 C5aR 减轻了 cGVHD 的病理学并改善了 cGVHD 小鼠的存活率。PMX53 对 Treg 的定向作用具有直接的调节作用，并增加了 TGF-β1 的表达。因此，C5aR 信号可能通过下调 Treg 的诱导而诱导和加剧 cGVHD。PMX53 对 C5aR 激活的调节可能为 cGVHD 提供一种潜在的治疗方法。
