M M Szachniewicz, K E van Meijgaarden, E Kavrik, W Jiskoot, J A Bouwstra, M C Haks, A Geluk, T H M Ottenhoff
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引用次数: 0
摘要
结核病(TB)是一个重大的全球健康问题,迫切需要开发有效、安全的疫苗。据推测,pH 值敏感脂质体可通过一种涉及 pH 值依赖性内体逸出和抗原胞浆转移的机制促进 I 类呈递,从而增强 CD8+ T 细胞的反应。本研究旨在探索 pH 值敏感脂质体作为一种新型递送系统在原代人体细胞中接种多阶段结核病蛋白亚单位疫苗的潜力。脂质体中加入了融合抗原 Ag85b-ESAT6-Rv2034 (AER),该抗原曾被证明能有效减少 HLA-DR3 转基因小鼠和豚鼠肺部的细菌负荷。在体外对脂质体的细胞摄取、细胞活力、细胞表面活化标志物的上调、使用人单核细胞衍生树突状细胞(MDDCs)诱导细胞因子的产生以及人抗原特异性 T 细胞的活化进行了评估。脂质体 DOPC:DOPE:DOBAQ:EPC(3:5:2:4 M 比率)能被有效吸收,诱导多种细胞表面活化标志物,并在 MDDCs 中产生 CCl3、CCL4 和 TNFα。它还能以抗原特异性的方式诱导 T 细胞克隆中 CD154 和 IFNγ 的上调。因此,基于阳离子 pH 敏感脂质体的结核病疫苗已被证明能够诱导强大的保护性 Mtb 特异性免疫反应,使其成为有效接种结核病疫苗的理想候选药物。
Cationic pH-sensitive liposomes as tuberculosis subunit vaccine delivery systems: Effect of liposome composition on cellular innate immune responses.
Tuberculosis (TB) is a major global health problem, and the development of effective and safe vaccines is urgently needed. CD8+ T-cells play an important role alongside CD4+ T-cells in the protective immune response against TB. pH-sensitive liposomes are hypothesized to boost CD8+ T-cell responses by promoting class I presentation through a mechanism involving pH-dependent endosomal escape and the cytosolic transfer of antigens. The aim of the study was to explore the potential of pH-sensitive liposomes as a novel delivery system for a multi-stage protein subunit vaccine against TB in primary human cells. The liposomes were formulated with the fusion antigen Ag85b-ESAT6-Rv2034 (AER), which was previously shown to be effective in reducing bacterial load in the lungs HLA-DR3 transgenic mice and guinea pigs. The liposomes were assessed in vitro for cellular uptake, cell viability, upregulation of cell surface activation markers, induction of cytokine production using human monocyte-derived dendritic cells (MDDCs), and activation of human antigen-specific T-cells. Liposome DOPC:DOPE:DOBAQ:EPC (3:5:2:4 M ratio) was effectively taken up, induced several cell surface activation markers, and production of CCl3, CCL4, and TNFα in MDDCs. It also induced upregulation of CD154 and IFNγ in T-cell clones in an antigen-specific manner. Thus, cationic pH-sensitive liposome-based TB vaccines have been demonstrated to be capable of inducing robust protective Mtb-specific immune responses, positioning them as promising candidates for effectiveTBvaccination.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.