Tumor Necrosis Factor-α and Interleukin-1 Antagonists Alleviate Inflammatory Skin Changes Associated with Epidermal Growth Factor Receptor Antibody Therapy in Mice
Tumor Necrosis Factor-α and Interleukin-1 Antagonists Alleviate Inflammatory Skin Changes Associated with Epidermal Growth Factor Receptor Antibody Therapy in Mice
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DOI：
10.1158/0008-5472.can-09-0487
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Tonra, James R.
中科院分区：
文献类型：
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作者：
Surguladze, David;Deevi, Dhanvanthri;Tonra, James R.
接受表皮生长因子受体(EGFR)抗体治疗的癌症患者经常在富含毛囊皮脂单位的皮肤区域出现病因不明的痤疮样皮疹。目前，这种情况的对症治疗非常有限，通常是坊间传闻的成功。在这里，我们展示了一种针对小鼠EGFR的单抗ME1，在小鼠中引起了中性粒细胞丰富的毛囊炎症，类似于在患者中的报道。在此之前，皮脂腺附近出现了充满脂肪的毛囊膨胀。细胞因子肿瘤坏死因子-α(肿瘤坏死因子-α)，免疫组织化学定位于毛皮脂腺单位的这一受影响区域，在皮肤中被ME1特异性上调，但在被检查的其他组织中不表达。此外，与肿瘤坏死因子α信号抑制剂依那西普联合治疗可减轻皮肤炎症，这表明肿瘤坏死因子α参与了这一炎症过程。白介素1是一种经常与肿瘤坏死因子α协同作用的细胞因子，考虑到白介素1拮抗剂Kineet的疗效，它也参与了这一过程。我们的结果为癌症患者中EGFR抗体诱导的皮疹的循证试验提供了一个机械框架。[癌症资源2009；69(14)：5643-7]
Cancer patients receiving epidermal growth factor receptor (EGFR) antibody therapy often experience an acneiform rash of uncertain etiology in skin regions rich in pilosebaceous units. Currently, this condition is treated symptomatically with very limited, often anecdotal success. Here, we show that a monoclonal antibody targeting murine EGFR, ME1, caused a neutrophil-rich hair follicle inflammation in mice, similar to that reported in patients. This effect was preceded by the appearance of lipid-filled hair follicle distensions adjacent to enlarged sebaceous glands. The cytokine tumor necrosis factor-alpha (TNF alpha), localized immunohistochemically to this affected region of the pilosebaceous unit, was specifically upregulated by ME1 in skin but not in other tissues examined. Moreover, skin inflammation was reduced by cotreatment with the TNF alpha signaling inhibitor, etanercept, indicating the involvement of TNF alpha in this inflammatory process. Interleukin-1, a cytokine that frequently acts in concert with TNF alpha, is also involved in this process given the efficacy of the interleukin-1 antagonist Kineret. Our results provide a mechanistic framework to develop evidence-based trials for EGFR antibody-induced skin rash in patients with cancer. [Cancer Res 2009;69(14):5643-7]