Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes
Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes
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DOI：
10.1182/blood-2011-07-368027
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发表时间：
2012-01-12
期刊：
影响因子：
20.3
通讯作者：
Blazar, Bruce R.
中科院分区：
文献类型：
--
作者：
Hippen, Keli L.;Bucher, Christoph;Blazar, Bruce R.
在啮齿动物移植物抗宿主病(GVHD)模型中，抗IL-21中和单抗治疗可改善致死率，并与Th1细胞因子的产生减少和胃肠道损伤有关。GVHD的预防依赖于体内产生供体诱导的调节性T细胞(Tregs)。为了确定IL-21途径是否可能作为GVHD预防的靶点，对无GVHD或2~4级GVHD患者的皮肤和结肠标本进行了IL-21蛋白表达的分析。免疫组织化学染色显示，GVHD患者的胃肠道标本和54%的皮肤标本中均有IL-21蛋白生成细胞表达，而非GVHD患者的皮肤标本中未检测到IL-21蛋白生成细胞。在人类异种GVHD模型中，人类IL-21分泌细胞存在于GVHD受者的结肠中，并与血清IL-21水平升高有关。预防性给予中和抗人IL-21单抗可显著减少GVHD相关的体重减轻和死亡率，导致Tregs增加，分泌干扰素-γ或颗粒酶B的T细胞减少。基于这些发现，抗IL-21单抗可用于临床预防GVHD。(血。2012年；119(2)：619-628)
In rodent graft-versus-host disease (GVHD) models, anti-IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls. In a human xenogeneic GVHD model, human IL-21-secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels. A neutralizing anti-human IL-21 mAb given prophylactically significantly reduced GVHD-associated weight loss and mortality, resulting in a concomitant increase in Tregs and a decrease in T cells secreting IFN-gamma or granzyme B. Based on these findings, anti-IL-21 mAb could be considered for GVHD prevention in the clinic. (Blood. 2012; 119(2): 619-628)