Silencing TNFα activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts:: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice
Silencing TNFα activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts:: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice
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DOI：
10.1007/s00441-005-1102-z
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发表时间：
2005-06-01
影响因子：
3.6
通讯作者：
Hodgetts, S
中科院分区：
文献类型：
--
作者：
Grounds, MD;Davies, M;Hodgetts, S
慢性炎症性疾病治疗的巨大临床成功归功于抗细胞因子疗法的使用，包括特异性阻断抗体、可溶性受体和陷阱，以沉默肿瘤坏死因子α（TNF α）和白细胞介素等炎症细胞因子的作用1（IL-1）。临床上用于阻断TNF α蛋白功能活性的两种药物是Remicade（一种抗体）和Enbrel（一种可溶性TNF受体）。这些工具现在正在扩展到许多其他临床疾病。我们对肌肉疾病的治疗特别感兴趣。为了研究新型抗细胞因子药物对人类疾病小鼠模型的作用，必须研究这些药物以确定它们是否确实有效地阻断小鼠中的炎症反应。这已经通过简单的体内生物测定进行。移植后5天采集的C57 BL/10 ScSn小鼠全肌肉自体移植物横切面的组织学检查提供了极好的试验模型，并清楚地表明类克和Enbrel阻断了体内急性炎症细胞反应。该移植物模型也已被用于表明，当在试验前1周甚至4周给药时，单次腹膜内注射类克（10 μ g/g）是长期有效的。当在肌肉移植前-3天和-1天注射两次（2x 100 μ g）时，Enbrel是高度有效的，但在移植前1周单次注射（100 μ g）后没有显示出对炎症反应的抑制。这种通过药理学阻断TNF α的炎症显著消融与TNF α缺失小鼠中缺乏任何作用形成鲜明对比。这种简单的可重复的小鼠体内试验模型可用于评估许多旨在阻断炎症的新型抗细胞因子干预措施的功效。
Dramatic clinical success in the treatment of chronic inflammatory diseases has resulted from the use of anti-cytokine therapies including specific blocking antibodies, soluble receptors and traps to silence the actions of inflammatory cytokines such as tumour necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1). Two agents used clinically to block the functional activity of TNF alpha protein are Remicade (an antibody) and Enbrel (a soluble TNF receptor). These tools are now being extended to many other clinical disorders. We have a specific interest in the treatment of muscle diseases. In order to study the effects of novel anti-cytokine drugs on mouse models of human disease, such drugs must be investigated to determine whether they are indeed effective in blocking the inflammatory response in mouse. This has been carried out by means of a simple in vivo bioassay. Histological examination of transverse sections from whole muscle autografts in C57BL/10ScSn mice sampled at 5 days after transplantation provides an excellent assay model and clearly shows that Remicade and Enbrel block the acute inflammatory cell response in vivo. This graft model has also been used to show that a single intraperitoneal injection of Remicade (10 mu g/g) is long-lived and effective when administered at 1 week and even 4 weeks prior to the assay. Enbrel is highly effective when injected twice at -3 days and -1 day (2x100 mu g) before muscle grafting but shows no inhibition of the inflammatory response after a single injection (100 mu g) 1 week prior to grafting. This striking ablation of inflammation by pharmacological blockage of TNF alpha is in marked contrast to the lack of any effect in TNF alpha null mice. This simple reproducible in vivo assay model in mice can be used to evaluate the efficacy of many novel anti-cytokine interventions designed to block inflammation.