Small cationic antimicrobial peptides: activators of innate & adaptive immunity

小阳离子抗菌肽：先天性激活剂

• 批准号: 7690534
• 负责人: Soman N Abraham
• 金额: $ 39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690534
• 关键词: Adjuvant; Adjuvanticity; Amino Acids; Antibodies; Antigens; Antimicrobial Cationic Peptides; Bacteria; Bioterrorism; Blood Circulation; Cells; Cholera Toxin; Class; Defensins; Dendritic Cells; Development; Epithelial Cells; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Infection; Infectious Agent; Length; Life; Ligands; Lymphocyte; Mammals; Mediator of activation protein; Mus; Nasal cavity; Nose; Numbers; Ovalbumin; Parasites; Pathologic; Peptides; Phagocytes; Production; Property; Proteins; Reporting; Safety; Serum; Site; Toll-like receptors; Toxic effect; Toxin; Vaccine Adjuvant; Vaccines; Virus; anthrax protective factor; antimicrobial; antimicrobial drug; antimicrobial peptide; base; fungus; interest; lymph nodes; migration; size; small molecule; synthetic peptide; trafficking

Cationic antimicrobial peptides, which are 100 amino acids or less in chain size, are produced in all living species. In mammals, they are primarily associated with mucosal epithelial cells and phagocytic cells. These peptides are produced in large amounts at sites of infection and have a broad spectrum of activity not only against gram negative and positive bacteria but also against fungi, viruses and parasites. Seven years ago, it was reported that co-administration of a cationic peptide (human defensin HNP1-3) with ovalbumin (ova), a nonimmunogenic protein, resulted in enhanced production of ova specific IgG antibodies () suggesting that these peptides possess intrinsic adjuvant properties. We have extended these studies employing much smaller peptides (~15 amino acids in length) and shown that co-instilling protective antigen (PA) of anthrax with small antimicrobial peptides into the nasal cavities of mice resulted in markedly elevated levels of PA-specific protective antibodies in the serum. Interestingly, the cationic peptides induced immune responses that were markedly superior to those induced by the powerful mucosal adjuvant cholera toxin that cannot be developed for use in humans because of its toxicity. No systemic or local pathologic effects were observed in mice immunized with small peptides. Antibodies specific for the cationic peptides, that may block its adjuvant activity if used repeatedly, were not detected. The adjuvanticity of these cationic peptides was associated with massive migration of dendritic cells from sites of instillation to the draining lymph nodes (DLNs) and large scale sequestration in the DLNs of lymphocytes from the circulation. Our findings support a growing number of studies suggesting that in addition to their antimicrobial functions, these cationic peptides may have the capacity to act on cells of the innate and adaptive immune system and regulate their activity. The specific aims of this proposal are to (i) demonstrate the efficacy and safety of small cationic peptides when used as nasal vaccine adjuvants (ii) elucidate the underlying immunological basis for adjuvant activity of cationic peptides.

在所有生存中都会产生阳离子抗菌肽，链尺寸为100氨基酸或更少 物种。在哺乳动物中，它们主要与粘膜上皮细胞和吞噬细胞有关。这些 肽在感染部位大量生产，并且具有广泛的活性 针对革兰氏阴性和阳性细菌，但也针对真菌，病毒和寄生虫。七年前，它 据报道，阳离子肽（人防御素HNP1-3）与卵蛋白（OVA）共同给药，A 非免疫原性蛋白，导致OVA特异性IgG抗体的产生增强，这表明 这些肽具有内在的辅助特性。我们已经扩展了这些研究的较小 肽（长度约为15个氨基酸），表明炭疽病的保护性抗原（PA）与小 抗菌肽进入小鼠的鼻腔腔，导致PA特异性水平明显升高 血清中的保护性抗体。有趣的是，阳离子肽诱导的免疫反应 明显优于强大的粘膜辅助霍乱毒素所诱导的那些，无法开发 由于其毒性而用于人类。在小鼠中未观察到全身或局部病理效应 用小肽免疫。对阳离子肽特异的抗体，可能会阻止其佐剂 活动如果反复使用，则未检测到。这些阳离子肽的辅助性与 树突状细胞从灌输部位迁移到排水淋巴结（DLN）和大规模迁移 循环中淋巴细胞DLN中的隔离。我们的发现支持越来越多的 研究表明，除了其抗菌功能外，这些阳离子肽可能具有 对先天和适应性免疫系统细胞作用并调节其活性的能力。具体目标 该建议的是（i）证明用作鼻腔时小阳离子肽的功效和安全性 疫苗佐剂（II）阐明了阳离子肽辅助活性的基本免疫学基础。