Division of Stem Cell and Bone Marrow Transplantation, Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
J Immunol. 2011 Nov 15;187(10):5130-40. doi: 10.4049/jimmunol.1101334. Epub 2011 Oct 17.
Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant immunosuppressive drugs incompletely control GVHD and increase susceptibility to opportunistic infections. In this study, we used flagellin, a TLR5 agonist protein (∼50 kDa) extracted from bacterial flagella, as a novel experimental treatment strategy to reduce both acute and chronic GVHD in allogeneic HSCT recipients. On the basis of the radioprotective effects of flagellin, we hypothesized that flagellin could ameliorate GVHD in lethally irradiated murine models of allogeneic HSCT. Two doses of highly purified flagellin (administered 3 h before irradiation and 24 h after HSCT) reduced GVHD and led to better survival in both H-2(b) → CB6F1 and H-2(K) → B6 allogeneic HSCT models while preserving >99% donor T cell chimerism. Flagellin treatment preserved long-term posttransplant immune reconstitution characterized by more donor thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells and significantly enhanced antiviral immunity after murine CMV infection. The proliferation index and activation status of donor spleen-derived T cells and serum concentration of proinflammatory cytokines in flagellin-treated recipients were reduced significantly within 4 d posttransplant compared with those of the PBS-treated control recipients. Allogeneic transplantation of radiation chimeras previously engrafted with TLR5 knockout hematopoietic cells showed that interactions between flagellin and TLR5 expressed on both donor hematopoietic and host nonhematopoietic cells were required to reduce GVHD. Thus, the peritransplant administration of flagellin is a novel therapeutic approach to control GVHD while preserving posttransplant donor immunity.
移植物抗宿主病（GVHD）是接受异基因造血干细胞移植（HSCT）治疗的患者发病和死亡的主要原因。移植后免疫抑制药物不能完全控制 GVHD，并且增加了机会性感染的易感性。在这项研究中，我们使用鞭毛蛋白（一种从细菌鞭毛中提取的 TLR5 激动蛋白（约 50 kDa））作为一种新的实验治疗策略，以减少异基因 HSCT 受者的急性和慢性 GVHD。基于鞭毛蛋白的放射保护作用，我们假设鞭毛蛋白可以改善致死性照射的异基因 HSCT 小鼠模型中的 GVHD。两次给予高纯度鞭毛蛋白（照射前 3 小时和 HSCT 后 24 小时给予）可减轻 H-2（b）→CB6F1 和 H-2（K）→B6 异基因 HSCT 模型中的 GVHD，并改善存活率，同时保留>99%的供体 T 细胞嵌合体。鞭毛蛋白治疗可保留长期移植后免疫重建，表现为更多的供体胸腺衍生的 CD4+CD25+Foxp3+调节性 T 细胞，并在小鼠 CMV 感染后显著增强抗病毒免疫。与 PBS 处理的对照组受者相比，在移植后 4 d 内，接受鞭毛蛋白治疗的受者的供体脾源性 T 细胞的增殖指数和激活状态以及促炎细胞因子的血清浓度均显著降低。先前植入 TLR5 敲除造血细胞的辐射嵌合体的异基因移植显示，鞭毛蛋白与供体造血细胞和宿主非造血细胞上表达的 TLR5 之间的相互作用是减轻 GVHD 所必需的。因此，移植前给予鞭毛蛋白是一种控制 GVHD 同时保留移植后供体免疫的新治疗方法。
