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Phytobacterial lipopolysaccharides in Juzen-taiho-to

十善太凤堂中的植物细菌脂多糖

基本信息

批准号：
10686871
负责人：
AKIRA KAWAMURA
金额：
$ 11.7万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686871
关键词：
Acids Acquired Immunodeficiency Syndrome Affect Animals Anti-Infective Agents Anti-Inflammatory Agents Attenuated Bacteria Benign Biological Assay Cell Line Cells Chemical Agents Clinical Communicable Diseases Country Development Diamond Disease Drug resistance Endotoxins Environment Extramural Activities Formulation Funding Future Goals Herbal Medicine Hydrolysis Immune Immunity Immunocompromised Host Immunologics Immunotherapeutic agent Immunotherapy In Vitro Infection prevention Inflammation Inflammatory Invaded Japan Learning Lipid A Lipopolysaccharides Macrophage Mass Spectrum Analysis Microbial Drug Resistance Molecular Mus National Institute of Allergy and Infectious Disease Natural Immunity Oral Administration Outcome Pathway interactions Phytochemical Plants Research Research Personnel Resistance Role Safety Signal Pathway Signal Transduction Stomach Structure Testing Time Toxic effect Toxin Universities Vaccine Adjuvant Work analog clinical efficacy cytokine drug resistant microorganism expectation experience global health immune modulating agents immunoregulation in vivo in vivo Model microbial novel novel strategies novel therapeutics pathogen pre-clinical prevent programs

项目摘要

Microbial drug resistance is a serious threat to the global health. It is essential to explore new anti-infective strategies that avoid the emergence of new drug resistance. One promising approach is the host-directed immunotherapy, which aims at boosting the innate immunity to prevent/treat infectious diseases. The approach avoids the emergence of resistance by targeting the host instead of the pathogen. Several host-directed immunotherapeutics are currently in clinical use, including monophosphoryl lipid A (MPL), which is used as a vaccine adjuvant. While the concept is promising, there is one major challenge in the development of new immunotherapeutics. Stimulation of the innate immunity activates the signaling pathways for inflammation as well as for protective immunity. Although inflammation is important for rapid eradication of invading pathogens, its hyperactivation can be very harmful to the host. Thus, the challenge is how to control inflammation without compromising protective immunity. To find a new approach to safely promote protective immunity, the proposed SC3 project will examine Juzen-taiho-to (JTT), an immune-boosting herbal formulation with long- tested clinical efficacy and safety. Recently, our group found that the immunostimulatory activity of JTT arises from lipopolysaccharides (LPSs) of plant-associated bacteria. Since LPSs are pro-inflammatory toxins, JTT must have a mechanism to effectively control the pro-inflammatory pathway. The objective of the proposed SC3 project is to clarify the mechanism by which pro-inflammatory effect of LPSs is controlled in JTT. The central hypothesis is that the pro-inflammatory effect is controlled by dual mechanisms, namely, (1) the LPSs in JTT, which is administered orally, are hydrolyzed by the stomach acid to benign forms that can still promote protective immunity, and (2) anti-inflammatory phytochemicals in JTT selectively attenuate the pro- inflammatory effect without compromising protective immunity. Both of these mechanisms are based on our strong preliminary results. To accomplish the objective, the following aims will be pursued. Aim 1: Characterize the structures and immunological effects of acid-treated LPSs in JTT. A combination of mass spectrometry cell-based assays, and in vivo cytokine profiling will be employed to characterize the impact of acid-treatment on the structures and immunological effects of phytobacterial LPSs. Aim 2: Determine the roles of anti- inflammatory phytochemicals in JTT. Here, anti-inflammatory phytochemicals will be subjected to cell-based assays and in vivo cytokine profiling to determine their effects on inflammation and other immunological pathways. It is our expectation that the proposed work will reveal a time-tested, but hitherto uncharacterized, approach to generate safe immunotherapeutics, which will expand our ability to develop new anti-infective strategies that avoid microbial resistance. The developmental objective of the PI is to build a strong collaborative research program focused on the discovery of novel immunomodulatory agents. Based on the results obtained from the proposed SC3 project, the collaborative team will aggressively seek extramural funding for future studies.

微生物耐药性严重威胁着全球的健康。因此，有必要开发新的抗感染药物避免出现新的耐药性的策略。一种很有前途的方法是主机指导的免疫疗法，旨在增强先天免疫力以预防/治疗传染病。的方法通过靶向宿主而不是病原体来避免抗性的出现。多个主机导向免疫治疗剂目前在临床上使用，包括单磷酰脂质A（MPL），其用作免疫治疗剂。疫苗佐剂。虽然这一概念很有希望，但在开发新技术方面存在一个重大挑战。免疫治疗先天免疫的刺激激活炎症信号通路，以及保护性免疫。虽然炎症对于迅速根除入侵的病原体很重要，它的过度激活对宿主非常有害。因此，挑战是如何控制炎症，危及保护性免疫为了找到一种安全促进保护性免疫的新方法，拟议的SC 3项目将研究Juzen-taiho-to（JTT），一种增强免疫力的草药配方，临床疗效和安全性。最近，我们的小组发现JTT的免疫刺激活性增加，植物相关细菌的脂多糖（LPS）。由于LPS是促炎毒素，JTT 必须有一种机制来有效地控制促炎途径。建议的目标 SC 3项目旨在阐明JTT中LPS的促炎作用的控制机制。的中心假设是促炎作用受双重机制控制，即：（1）LPS 在口服的JTT中，被胃酸水解成良性形式，保护性免疫，（2）JTT中的抗炎植物化学物质选择性地减弱了促炎因子，炎症作用，而不损害保护性免疫。这两种机制都是基于我们的强劲的初步结果。为实现这一目标，将努力实现以下目标。目标1：表征 JTT中酸处理的脂多糖的结构和免疫作用。结合质谱分析将采用基于细胞的试验和体内细胞因子分析来表征酸处理的影响植物细菌脂多糖的结构和免疫学效应。目标2：确定抗- JTT中的炎性植物化学物质。在这里，抗炎植物化学物质将受到基于细胞的测定和体内细胞因子谱分析，以确定它们对炎症和其他免疫反应的影响。途径。我们期望，拟议的工作将揭示一个经过时间考验、但迄今为止尚未定性的，一种产生安全的免疫治疗药物的方法，这将扩大我们开发新的抗感染药物的能力。避免微生物耐药性的策略。PI的发展目标是建立一个强大的合作研究计划的重点是发现新的免疫调节剂。基于从拟议的SC 3项目获得的结果，合作团队将积极寻求校外为今后的研究提供资金。