De Benedetti F, Pignatti P, Vivarelli M, Meazza C, Ciliberto G, Savino R, Martini A
Dipartimento di Scienze Pediatriche, Instituto di Ricerca e Cura a Carattere Scientifico Policlinico San Matteo, Universita' degli Studi di Pavia, Pavia, Italy.
J Immunol. 2001 Apr 1;166(7):4334-40. doi: 10.4049/jimmunol.166.7.4334.
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.
在包括B细胞肿瘤、骨质疏松症和自身免疫性疾病在内的多种疾病中，中和白细胞介素-6（IL-6）是一种有吸引力的治疗选择。针对人类的治疗尝试表明，注射剂量的抗IL-6单克隆抗体（mAb）在体内并不能有效地中和细胞因子。因此，需要其他方法。在本研究中，我们评估了用Sant1（一种有七个氨基酸替换的hIL-6变体）接种疫苗引发的针对人IL-6（hIL-6）的抗体反应是否能够在体内完全纠正hIL-6转基因NSE/hIL-6小鼠中慢性内源性hIL-6过度产生的临床和生物学效应。由于自出生起就发生hIL-6的过表达，循环水平在每毫升纳克范围内，NSE/hIL-6小鼠的生长速率显著降低，与胰岛素样生长因子I水平降低相关，并且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免疫后，但用hIL-6免疫则不然，NSE/hIL-6小鼠产生了高滴度的针对hIL-6的多克隆抗体。通过胎盘转移获得的这些抗体在体内有效地中和了IL-6的活性，这在hIL-6转基因后代的生长缺陷完全纠正和胰岛素样生长因子水平正常化中得到了体现。因此，用Sant1免疫可能代表了一种针对人类特异性中和IL-6的新颖且简单的治疗方法。
