Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD
Blocking TWEAK-Fn14 interaction inhibits hematopoietic stem cell transplantation-induced intestinal cell death and reduces GVHD
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DOI：
10.1182/blood-2015-01-620583
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发表时间：
2015-07-23
期刊：
影响因子：
20.3
通讯作者：
Wajant, Harald
中科院分区：
文献类型：
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作者：
Chopra, Martin;Brandl, Andreas;Wajant, Harald
在几种结肠炎模型中，抑制肿瘤坏死因子(TNF)样的弱凋亡诱导因子(TWEY)/成纤维细胞生长因子诱导的14(Fn14)系统可减少肠道细胞死亡和疾病发展。鉴于肿瘤坏死因子和肠道细胞死亡在移植物抗宿主病(GVHD)中的重要作用，以及TWEEP增强肿瘤坏死因子诱导的细胞死亡的能力，我们检测了Fn14拮抗剂对异基因造血细胞移植(allo-HCT)诱导的肠道GVHD的治疗作用。具有抗体依赖细胞毒性(ADCC)活性的Fn14特异性封闭人免疫球蛋白G1抗体变体强烈抑制小鼠allo-HCT诱导的GVHD的严重程度。用该单抗治疗allo-HCT受者可减少胃肠道细胞的死亡，但不影响供者T细胞对器官的侵袭，也不影响细胞因子的产生。阻断Fn14还可抑制肿瘤坏死因子攻击小鼠的肠道细胞死亡。提示阻断Fn14对allo-HCT的保护作用是基于对肿瘤坏死因子诱导的肠细胞凋亡的保护作用，而不是通过免疫抑制。重要的是，阻断Fn14对移植物抗白血病/淋巴瘤(GVL)活性没有负面影响。因此，ADCC缺陷的Fn14阻断抗体不仅可能是治疗GVHD的新型GVL效应保留疗法，而且还可能用于治疗其他炎症性肠病，其中肿瘤坏死因子诱导的细胞死亡是相关的。
Inhibition of the tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) system reduces intestinal cell death and disease development in several models of colitis. In view of the crucial role of TNF and intestinal cell death in graft-versus-host disease (GVHD) and the ability of TWEAK to enhance TNF-induced cell death, we tested here the therapeutic potential of Fn14 blockade on allogeneic hematopoietic cell transplantation (allo-HCT)-induced intestinal GVHD. An Fn14-specific blocking human immunoglobulin G1 antibody variant with compromised antibody-dependent cellular cytotoxicity (ADCC) activity strongly inhibited the severity of murine allo-HCT-induced GVHD. Treatment of the allo-HCT recipients with this monoclonal antibody reduced cell death of gastrointestinal cells but neither affected organ infiltration by donor T cells nor cytokine production. Fn14 blockade also inhibited intestinal cell death in mice challenged with TNF. This suggests that the protective effect of Fn14 blockade in allo-HCT is based on the protection of intestinal cells from TNF-induced apoptosis and not due to immune suppression. Importantly, Fn14 blockade showed no negative effect on graft-versus-leukemia/lymphoma (GVL) activity. Thus, ADCC-defective Fn14-blocking antibodies are not only possible novel GVL effect-sparing therapeutics for the treatment of GVHD but might also be useful for the treatment of other inflammatory bowel diseases where TNF-induced cell death is of relevance.