MODULATION OF INNATE IMMUNE RESPONSES WITH SYNTHETIC LIPID A DERIVATIVES

用合成脂质 A 衍生物调节先天免疫反应

• 批准号: 7957528
• 负责人: Geert-Jan Boons
• 金额: $ 0.22万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957528
• 关键词: Accounting; Acylation; Affect; Asthma; Bacteria; Biological; Carbohydrates; Cell Wall; Clinical; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Disease; Escherichia coli; Fatty Acids; Funding; Future; Gram-Negative Bacteria; Grant; Heterogeneity; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Institution; Knowledge; Lead; Length; Lipid A; Lipids; Lipopolysaccharides; Malignant Neoplasms; Mediator of activation protein; Membrane; Modification; Molecular; Natural Immunity; Pattern; Phosphorylation; Research; Research Personnel; Resources; Salmonella typhimurium; Septic Shock; Source; Structure; Structure-Activity Relationship; Symptoms; Therapeutic; Time; Toxic effect; United States National Institutes of Health; Vaccine Adjuvant; Vertebral column; cytokine; design; in vivo; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Evidence is emerging that innate immune responses can be exploited for therapeutic purposes such as the development of adjuvants for vaccines and the treatment of a wide range of diseases including asthma, infection, and cancer. An important concern of such therapies is, however, that over-activation of innate immunity may lead to the clinical symptoms of septic shock. Thus, an important issue for the design of safe immune modulators is a detailed knowledge of structure-activity relationships to harness beneficial effects without causing toxicity. Lipopolysaccharides (LPS) are structural components of the outer membrane of Gram-negative bacteria that offer great promise for the development of immuno-modulators. It has been demonstrated unequivocally that lipid A is the inflammation-inducing moiety of LPS. Recent structural studies have shown that the carbohydrate backbone, degree of phosphorylation, and fatty acid acylation patterns of lipid A vary considerably among bacterial species. These structural differences probably account for the highly variable in vivo and in vitro host responses to LPS. There is also some indication that structurally different lipid As may differentially induce proinflammatory responses. Heterogeneity in the structure of lipid A within a particular bacterial strain and possible contamination with other inflammatory components of the bacterial cell-wall complicates the use of either LPS or lipid A isolated from bacteria to dissect the molecular mechanisms responsible for the biological responses to specific lipid A molecules. To determine whether the structure of lipid A can modulate innate immunological responses, we have synthesized a panel of lipid As derived from E. coli and S. typhimurium LPS that differ in acylation and phosphorylation pattern, and lipid length. We have determined the potencies and efficacies of a wide range of mediators induced by the well-defined lipid As. It was found that cellular activation with a particular compound can give potencies (EC50 values) for various mediators that can differ by as much as 100-fold. Furthermore, particular modifications affected the potencies of cytokines differently. Collectively, our data show for the first time that structurally different lipid As can induce distinct immune responses. This information is of critical importance for the future development of immuno-therapies.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 越来越多的证据表明，先天免疫反应可用于治疗目的，例如开发疫苗佐剂以及治疗包括哮喘、感染和癌症在内的多种疾病。 然而，此类疗法的一个重要问题是先天免疫的过度激活可能会导致 导致感染性休克的临床症状。因此，设计安全免疫调节剂的一个重要问题是详细了解结构-活性关系，以利用有益作用而不引起毒性。 脂多糖（LPS）是革兰氏阴性细菌外膜的结构成分，为免疫调节剂的开发提供了广阔的前景。 已明确证明脂质A 是LPS的炎症诱导部分。最近的结构研究表明，脂质 A 的碳水化合物主链、磷酸化程度和脂肪酸酰化模式在细菌种类之间存在很大差异。这些结构差异可能解释了体内和体外宿主的高度可变性 对 LPS 的反应。还有一些迹象表明，结构不同的脂质 As 可能会不同地诱导促炎反应。特定细菌菌株内脂质 A 结构的异质性以及可能受到细菌细胞壁其他炎症成分的污染，使得使用从细菌中分离的 LPS 或脂质 A 来剖析负责对特定脂质的生物反应的分子机制变得复杂一个分子。 为了确定脂质 A 的结构是否可以调节先天免疫反应，我们合成了一组源自大肠杆菌和鼠伤寒沙门氏菌 LPS 的脂质 As，它们在酰化和磷酸化模式以及脂质长度方面有所不同。我们已经确定了由明确的脂质 As 诱导的多种介质的效力和功效。研究发现，使用特定化合物激活细胞后，各种介质的效力（EC50 值）可能相差 100 倍。此外，特定的修饰对细胞因子的效力有不同的影响。总的来说，我们的数据首次表明结构不同的脂质 As 可以诱导不同的免疫反应。此信息至关重要 对于免疫疗法的未来发展具有重要意义。