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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >TNFα kinoid vaccination-induced neutralizing antibodies to TNFα protect mice from autologous TNFα-driven chronic and acute inflammation
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TNFα kinoid vaccination-induced neutralizing antibodies to TNFα protect mice from autologous TNFα-driven chronic and acute inflammation

机译：TNFα类固醇疫苗接种诱导的TNFα中和抗体可保护小鼠免受自体TNFα驱动的慢性和急性炎症

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摘要

The proinflammatory cytokine TNFα is a potent mediator of septic shock and a therapeutic target for chronic inflammatory pathologies including rheumatoid arthritis and Crohn's disease. As an alternative to anti-human TNFα (hTNFα) mAbs and other hTNFα blocker approved drugs, we developed an active anti-hTNFα immunotherapy, based on a vaccine comprised of a keyhole limpet hemocyanin-hTNFα heterocomplex immunogen (hTNFα kinoid) adjuvanted in incomplete Freund's adjuvant. In mice transgenic for hTNFα (TTg mice), hTNFα kinoid vaccination elicited high titers of Abs that neutralized hTNFα bioactivities but did not result in a cellular response to hTNFα. The vaccine was safe and effective in two experimental models. Kinoid-immunized but not control TTg mice resisted hTNFα-driven shock in one model and were prevented from spontaneous arthritis, inflammatory synovitis, and articular destruction in a second model. These data demonstrate an anti-cytokine induction of autoimmune protection against both acute and chronic hTNFα exposure. They show that active vaccination against a human cytokine can be achieved, and that the immune response can be effective and safe.
机译：促炎细胞因子TNFα是败血性休克的有效介体，是包括类风湿关节炎和克罗恩病在内的慢性炎症病理的治疗靶标。作为抗人TNFα（hTNFα）单克隆抗体和其他hTNFα阻断剂批准的药物的替代品，我们开发了一种主动的抗hTNFα免疫疗法，该疫苗基于包含在不完全弗氏佐剂中佐以的匙孔血蓝蛋白-hTNFα异源复合免疫原（hTNFαkinoid）的疫苗佐剂。在转染了hTNFα的小鼠（TTg小鼠）中，hTNFαkinoid疫苗接种引起了高滴度的Abs，该抗体中和了hTNFα的生物活性，但未引起对hTNFα的细胞应答。该疫苗在两个实验模型中是安全有效的。在一种模型中，经Kinoid免疫但未进行对照的TTg小鼠可抵抗hTNFα驱动的休克，在另一种模型中可预防自发性关节炎，炎性滑膜炎和关节破坏。这些数据证明了针对急性和慢性hTNFα暴露的自身免疫保护的抗细胞因子诱导。他们表明可以实现针对人细胞因子的主动疫苗接种，并且免疫反应可以是有效而安全的。

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