Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation.
Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation.
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DOI：
10.1158/1078-0432.ccr-10-1198
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发表时间：
2011-01-01
期刊：
影响因子：
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通讯作者：
Reddy P
中科院分区：
文献类型：
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作者：
Tawara I;Koyama M;Liu C;Toubai T;Thomas D;Evers R;Chockley P;Nieves E;Sun Y;Lowler KP;Malter C;Nishimoto N;Hill GR;Reddy P
移植物抗肿瘤（GVT）效应是针对许多血液恶性肿瘤和一些实体瘤的有效形式的免疫疗法。异基因骨髓移植（BMT）后的有益GVT效应与其最重要的并发症移植物抗宿主病（GVHD）密切相关。白细胞介素-6（IL-6）在异基因骨髓移植后的作用尚不清楚。本研究使用一系列互补敲除和抗体阻断策略来分析IL-6在多种临床相关的GVHD和GVT小鼠模型中的影响。我们通过分析IL-6缺乏在供体T细胞、供体骨髓或宿主组织中的作用来检查IL-6来源的影响。我们通过用抗小鼠IL-6受体（IL-6 R）MR 16 -1治疗BMT受体，证实并扩展了IL-6缺乏与GVHD和GVT的相关性。供体T细胞中IL-6的缺乏导致生存期延长。用MR 16 -1完全抑制IL-6引起GVHD诱导的死亡率的更大降低。GVHD的减少不依赖于对T效应细胞扩增或供体调节性T细胞的直接影响。在用MR 16 -1处理后，GVT反应得以保留。MR 16 -1治疗减少了GVHD并保留了足够的GVT。Tocilizumab是一种人源化抗IL-6 R mAb，已在包括美国和欧盟在内的多个国家获批用于治疗类风湿性关节炎和其他炎性疾病。抗IL-6 R mAb疗法阻断IL-6可以在临床试验中进行测试，作为预防BMT患者GVHD的辅助手段，而不会显着损失GVT。
The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematological malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well-understood. This study used a series of complementary knock-out and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT. We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on GVHD and GVT by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1. Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1. MR16-1 treatment reduced GVHD and preserved sufficient GVT. Tocilizumab, a humanized anti-IL-6R mAb, is approved in several countries including the United States and European Union for the treatment of rheumatoid arthritis and other inflammatory diseases. Blockade of IL-6 with anti-IL-6R mAb therapy may be testable in clinical trials as an adjunct to prevent GVHD in BMT patients without a significant loss of GVT.