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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination
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In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

机译：在计算机中鉴定出的CCR4拮抗剂靶向调节性T细胞并在疫苗接种中发挥佐剂活性

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Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4+CD25+ regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4+ T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4+ T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.
机译：佐剂是增强免疫反应从而提高疫苗接种效力的物质。很少有佐剂可用于人类，最常用的佐剂（alum）通常会诱导次佳免疫力，以抵抗多种病原体。因此，显然需要开发新的和改进的佐剂。因此，我们采用了一种在计算机模拟和基于结构的药物设计中使用的佐剂发现方法。作为原理的证明，我们选择靶向趋化因子CCL22和CCL17与其受体CCR4的相互作用。基于CCR4在CD4 + CD25 + 调节性T细胞（Tregs）上的表达，它被定位为佐剂靶标，从而负调节树突状细胞（DC）诱导的免疫反应， CCL17和CCL22是DC产生的趋化剂，对于促进DC与CCR4 + T细胞之间的接触至关重要。通过虚拟筛选和分子对接鉴定为CCR4拮抗剂的分子能够阻断CCL22和CCL17介导的人类Tregs和Th2细胞募集。此外，CCR4拮抗剂与修饰的牛痘表达素组合使用时，可在体外免疫应答模型中增强DC介导的人CD4 + T细胞增殖，并在实验模型中增强体内细胞和体液免疫应答。来自结核分枝杆菌（MVA85A）的Ag85A或重组乙型肝炎病毒表面抗原（rHBsAg）疫苗。观察到的重要佐剂活性提供了良好的证据，支持了我们的假设，即CCR4是合理佐剂设计的可行目标。

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