Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity.
Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity.
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DOI：
10.4049/jimmunol.1101334
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发表时间：
2011-11-15
期刊：
影响因子：
--
通讯作者：
Waller EK
中科院分区：
文献类型：
--
作者：
Hossain MS;Jaye DL;Pollack BP;Farris AB;Tselanyane ML;David E;Roback JD;Gewirtz AT;Waller EK
移植物抗宿主病（GvHD）是异基因造血干细胞移植（HSCT）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，并增加对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TLR 5激动剂蛋白（~50 kDa），作为一种新的实验性治疗策略，以减少同种异体HSCT受体的急性和慢性GvHD。基于鞭毛蛋白的辐射保护作用，我们假设鞭毛蛋白可以改善致死剂量照射的同种异体HSCT小鼠模型中的GvHD。两个剂量的高度纯化的鞭毛蛋白（给药3小时。辐照前和辐照后24小时。HSCT后）减少GvHD，并导致H-2b → CB 6 F1和H-2k → B6同种异体HSCT模型中更好的存活，同时保留超过99%的供体T细胞嵌合体。鞭毛蛋白治疗保留了长期的移植后免疫重建，其特征在于更多的供体胸腺来源的CD 4 + CD 25 + foxp 3+调节性T细胞（TCFs），并显著增强了鼠巨细胞病毒（mCMV）感染模型后的抗病毒免疫。与PBS治疗的对照受者相比，鞭毛蛋白治疗的受者中供体脾源性T细胞的增殖指数和活化状态以及促炎细胞因子的血清浓度在移植后4天内显着降低。先前植入TLR 5敲除造血细胞的辐射嵌合体的同种异体移植表明，需要鞭毛蛋白和供体造血细胞和宿主非造血细胞上表达的TLR 5之间的相互作用来减少GvHD。因此，在移植物周围施用鞭毛蛋白是控制GvHD同时保持移植后供体免疫的新的治疗方法。
Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Post-transplant 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 recipient. Based upon the radio-protective 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 hrs. before irradiation and 24 hrs. after HSCT) reduced GvHD and led to better survival in both H-2b → CB6F1 and H-2k → B6 allogeneic HSCT models while preserving over 99% donor T cells chimerism. Flagellin treatment preserved long-term post-transplant immune reconstitution characterized by more donor thymic-derived CD4+CD25+foxp3+ regulatory T cells (Tregs) and significantly enhanced anti-viral immunity following murine cytomegalovirus (mCMV) infection model. The proliferation index and activation status of donor spleen-derived T cells, and serum concentration of pro-inflammatory cytokines in flagellin-treated recipients were reduced significantly within 4 days post-transplant compared with 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 non-hematopoietic cells were required to reduce GvHD. Thus, the peri-transplant administration of flagellin is a novel therapeutic approach control GvHD while preserving post-transplant donor immunity.
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