Antigen-presenting cell-derived complement modulates graft-versus-host disease
Antigen-presenting cell-derived complement modulates graft-versus-host disease
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DOI：
10.1172/jci61019
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发表时间：
2012-06-01
影响因子：
15.9
通讯作者：
Heeger, Peter S.
中科院分区：
文献类型：
--
作者：
Kwan, Wing-Hong;Hashimoto, Daigo;Heeger, Peter S.
急性移植物抗宿主病（GvHD）是异基因造血细胞移植（allo-HCT）的严重并发症，由供体异基因T细胞攻击宿主组织引起。基于先前的工作涉及免疫细胞衍生的C3 a和C5 a作为T细胞免疫的调节剂，我们检查了局部产生的C3 a和C5 a对小鼠T细胞介导的GvHD的影响。我们发现，全身照射，一种允许allo-HCT植入所需的预处理方案，引起受体APC上调和激活旁路途径补体成分。具有衰变加速因子无效（Daf 1（-/-））宿主BM和Daf 1（-/-）供体淋巴细胞的Allo-HCT导致GvHD结局恶化，并导致脾脏和器官浸润T细胞扩增。C3 a受体（C3 aR）和/或C5 a受体（C5 aR）缺陷的T细胞在同种异体宿主中反应弱，并且表现出有限的诱导GvHD的能力。使用临床相关的治疗策略，我们表明，药理学C5 aR阻断降低GvHD发病率。我们的数据将APC衍生的补体与T细胞介导的GvHD机械地联系起来，并支持补体抑制作为人类GvHD的治疗策略。
Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1(-/-)) host BM and Daf1(-/-) donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.