In vivo neutralization of human IL-6 (hIL-6) achieved by immunization of hIL-6-transgenic mice with a hIL-6 receptor antagonist
In vivo neutralization of human IL-6 (hIL-6) achieved by immunization of hIL-6-transgenic mice with a hIL-6 receptor antagonist
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DOI：
10.4049/jimmunol.166.7.4334
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发表时间：
2001-04-01
影响因子：
4.4
通讯作者：
Martini, A
中科院分区：
文献类型：
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作者：
De Benedetti, F;Pignatti, P;Martini, A
白细胞介素-6的中和在包括B细胞瘤、骨质疏松和自身免疫在内的几种疾病中是一种有吸引力的治疗选择。人类的治疗尝试表明，注射剂量的单抗对IL-6并不能有效地在体内中和细胞因子。因此，需要其他方法。在这项研究中，我们评估了通过接种Sant1（一种具有7个氨基酸取代的hIL-6变体）引起的抗体对人IL-6 （hIL-6）的反应是否能够在体内完全纠正hIL-6转基因NSE/hIL-6小鼠慢性内源性过量生产hIL-6的临床和生物学效应。由于hIL-6自出生以来就过度表达，循环水平在纳克/毫升范围内，NSE/hIL-6小鼠的生长速度明显下降，并伴有胰岛素样生长因子I水平的下降，代表了与人类慢性炎症性疾病相关的生长障碍的动物模型。用Sant1而非hIL-6免疫后，NSE/hIL-6小鼠对hIL-6产生高滴度的多克隆抗体。经胎盘移植获得的抗体在体内有效地中和了IL-6的活性，结果表明，IL-6转基因后代的生长缺陷得到完全纠正，胰岛素样生长因子水平正常化。因此，Sant1免疫可以代表一种新的、简单的治疗方法，用于人类特异性中和IL-6。
Neutralization of IL-6 represents an attractive therapeutic option in several diseases, including B cell neoplasia, osteoporosis, and autoimmunity. Therapeutic attempts in humans have shown that administration of injectable doses of a mAb to IL-6 does not provide efficient neutralization of the cytokine in vivo. Therefore, alternative approaches are needed. In this study, we evaluated whether the Ab response to human IL-6 (hIL-6) elicited by vaccination with Sant1 (a hIL-6 variant with seven amino acid substitutions) was able to fully correct in vivo the clinical and biological effects of a chronic endogenous overproduction of hIL-6 in the hIL-6-transgenic NSE/hIL-6 mice. Because of the overexpression of hIL-6, occurring since birth, with circulating levels in the nanogram per milliliter range, NSE/hIL-6 mice have a marked decrease in growth rate, associated with decrease in insulin-like growth factor I levels, and represent an animal model of the growth impairment associated with human chronic inflammatory diseases. Following immunization with Sant1, but not with hIL-6, NSE/hIL-6 mice developed high titers of polyclonal Abs to hIL-6. The Abs, acquired by transplacental transfer, effectively neutralized IL-6 activities in vivo as shown by the complete correction of the growth defect and normalization of insulin-like growth factor levels in the hIL-6-transgenic offspring. Immunization with Sant1 could therefore represent a novel and simple therapeutic approach for the specific neutralization of IL-6 in humans.