Zuany-Amorim Claudia, Manlius Corinne, Dalum Iben, Jensen Martin R, Gautam Anand, Pay Graham, Mouritsen Søren, Walker Christoph
Novartis Horsham Research Centre, Novartis Pharmaceutical Ltd, Horsham, UK.
Int Arch Allergy Immunol. 2004 Feb;133(2):154-63. doi: 10.1159/000076441. Epub 2004 Jan 26.
Cytokines play an integral role in the coordination and persistence of allergic inflammatory processes and therefore represent prime targets for novel therapies in diseases such as asthma. Multiple attempts to generate low-molecular-weight cytokine inhibitors have failed, and the main attention has focused on the development of biological agents such as neutralizing antibodies. The present work describes a simple and effective method to induce the production of therapeutic anti-cytokine autoantibodies by active immunization against a modified endogenous cytokine.
Balb/c mice were subcutaneously injected with AutoVac TNF106, a recombinant murine TNF-alpha molecule containing a foreign immunogenic T helper epitope, and the induction of neutralizing anti-TNF-alpha autoantibodies was analysed. These mice were then sensitized with ovalbumin (OVA), and the effect of neutralizing anti-TNF-alpha autoantibodies on the allergen-induced airway inflammation was analysed.
AutoVac TNF106-immunized mice developed high titres of neutralizing anti-TNF-alpha autoantibodies, which were maintained for at least 4 weeks after the last booster injection. Mice vaccinated with AutoVac TNF106 and further immunized against OVA showed diminished TNF-alpha levels in the bronchoalveolar lavage (BAL) fluid after OVA challenge. Moreover, pretreatment with AutoVac TNF106 resulted in significantly reduced numbers of eosinophils and neutrophils in BAL fluid in response to single or multiple allergen exposure.
The induction of anti-TNF-alpha autoantibody production by the AutoVac TNF106 technology not only confirmed the role of TNF-alpha in the induction of allergic inflammation but also offers a novel approach to block the activity of cytokines in order to treat allergic inflammatory conditions.
细胞因子在过敏性炎症过程的协调和持续中发挥着不可或缺的作用，因此是哮喘等疾病新型疗法的主要靶点。多次尝试生成低分子量细胞因子抑制剂均告失败，主要注意力集中在生物制剂如中和抗体的研发上。本研究描述了一种通过针对修饰后的内源性细胞因子进行主动免疫来诱导产生治疗性抗细胞因子自身抗体的简单有效方法。
给Balb/c小鼠皮下注射AutoVac TNF106，这是一种含有外来免疫原性T辅助表位的重组鼠肿瘤坏死因子-α分子，分析中和性抗肿瘤坏死因子-α自身抗体的诱导情况。然后用卵清蛋白（OVA）使这些小鼠致敏，分析中和性抗肿瘤坏死因子-α自身抗体对变应原诱导的气道炎症的影响。
用AutoVac TNF106免疫的小鼠产生了高滴度的中和性抗肿瘤坏死因子-α自身抗体，在最后一次加强注射后至少维持4周。用AutoVac TNF106接种并进一步针对OVA免疫的小鼠在OVA激发后支气管肺泡灌洗（BAL）液中的肿瘤坏死因子-α水平降低。此外，用AutoVac TNF106预处理导致单次或多次变应原暴露后BAL液中嗜酸性粒细胞和中性粒细胞数量显著减少。
AutoVac TNF106技术诱导抗肿瘤坏死因子-α自身抗体产生不仅证实了肿瘤坏死因子-α在变应性炎症诱导中的作用，还提供了一种阻断细胞因子活性以治疗变应性炎症性疾病的新方法。
