Achievement of a synergistic adjuvant effect on arthritis induction by activation of innate immunity and forcing the immune response toward the Th1 phenotype
Achievement of a synergistic adjuvant effect on arthritis induction by activation of innate immunity and forcing the immune response toward the Th1 phenotype
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DOI：
10.1002/art.20180
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发表时间：
2004-05-01
影响因子：
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通讯作者：
Glant, TT
中科院分区：
文献类型：
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作者：
Hanyecz, A;Berlo, SE;Glant, TT
目标。目的：应用和分析二甲基二十八烷基溴化铵(DDA)在蛋白多糖诱导的关节炎(PGIA)和胶原诱导的关节炎(CIA)中的作用机制。用软骨蛋白多糖(PG)或人II型胶原(CII)与弗氏完全佐剂(CFA)乳化的标准免疫方案产生PGIA和CIA，并与相同抗原与佐剂DDA联合使用的免疫方案产生的PGIA和CIA进行比较。在整个实验过程中，对免疫和自身PGs和CII的免疫反应以及关节炎的发生率、严重性和发病进行了监测。此外，还描述了一种新的、廉价的、有效的利用软骨粗提物诱导关节炎的方法。软骨PGs在DDA免疫BALB/c小鼠后，发病时间明显缩短，关节炎程度加重。在BALB/c小鼠中，来自牛、羊和猪软骨的PGS没有任何作用或仅有亚关节炎作用，而人骨关节炎软骨的粗提物在BALB/c小鼠中诱导100%的发病率和非常高的关节炎评分。在抗原/CFA免疫和抗原/DDA免疫的动物中，对CII或PG的整体免疫应答相似，但在注射DDA的动物中，无论是PGIA还是CIA，Th1/Th2平衡明显偏向Th1。DDA最初用于自身免疫模型，是一种有效的非刺激性佐剂，它消除了弗氏佐剂的所有不良副作用。DDA通过激活非特异性(先天)免疫发挥强大的刺激作用，迫使免疫调节向Th1占优势方向发展。这些证据还表明，看似无害的化合物可能对人类起到佐剂作用，并可能通过激活/刺激天然免疫为易感个体创造自身免疫的病理生理学基础。
Objective. To apply and analyze the mechanisms of action of dimethyldioctadecylammonium bromide (DDA), a powerful adjuvant that does not have the side effects of the conventionally used Freund's adjuvants, in proteoglycan-induced arthritis (PGIA) and collagen-induced arthritis (CIA).Methods. PGIA and CIA were generated using standard immunization protocols with cartilage proteoglycan aggrecan (PG) or human type II collagen (CII) emulsified with Freund's complete adjuvant (CFA), and compared with PGIA and CIA generated using immunization protocols in which the same antigens were used in combination with the adjuvant DDA. Immune responses to immunizing and self PGs and CII, and the incidence, severity, and onset of arthritis were monitored throughout the experiments. In addition, a new, inexpensive, and powerful method of inducing arthritis using crude cartilage extracts is described.Results. A significantly reduced onset period and a more severe arthritis were achieved in BALB/c mice immunized with cartilage PGs in DDA. PGs from bovine, ovine, and porcine cartilage, which otherwise have no effect or have only a subarthritogenic effect, and crude extracts of human osteoarthritic cartilage induced a 100% incidence with a very high arthritis score in BALB/c mice. The overall immune responses to either CII or PG were similar in antigen/CFA-immunized and antigen/DDA-immunized animals, but the Th1/Th2 balance shifted significantly toward a Th1 bias in DDA-injected animals with either PGIA or CIA.Conclusion. DDA, which was first used in autoimmune models, is a potent nonirritant adjuvant, which eliminates all undesired side effects of the Freund's adjuvants. DDA exerts a strong stimulatory effect via the activation of nonspecific (innate) immunity and forces the immune regulation toward Th1 dominance. These lines of evidence also suggest the possibility that seemingly innocuous compounds may exert an adjuvant effect in humans and may create the pathophysiologic basis of autoimmunity in susceptible individuals via the activation/stimulation of innate immunity.