Lactoferrin as an Adjuvant for Cellular Immunity

乳铁蛋白作为细胞免疫佐剂

• 批准号: 7054057
• 负责人: JEFFREY K ACTOR
• 金额: $ 40.53万
• 依托单位: PHARMAREVIEW CORPORATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-11-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054057
• 关键词: Bacillus Calmette Guerin vaccine; CHO cells; Mycobacterium tuberculosis; New World Arenavirus; SDS polyacrylamide gel electrophoresis; bacterial antigens; cellular immunity; drug screening /evaluation; enzyme linked immunosorbent assay; high performance liquid chromatography; immunomodulators; interferon gamma; interleukin 12; interleukin 2; laboratory mouse; lactoferrin; leukocyte activation /transformation; matrix assisted laser desorption ionization; polymerase chain reaction; proteomics; recombinant proteins; tuberculosis; vaccine evaluation

DESCRIPTION (provided by applicant): The overall goal of this project is to develop human recombinant Lactoferrin as an adjuvant to BCG to augment cell mediated immunity (CMI) and protect alveolar integrity upon infection with Mycobacterium tuberculosis. Improved nontoxic adjuvants, especially adjuvants capable of inducing CMI, are needed for research in immunology and for development of human and veterinary vaccines. This is especially true for development of vaccines to combat tuberculosis, where efficacy of the bacille Calmette-Guerin strain of M. bovis (BCG) as a vaccine has been unsuccessful to curtail worldwide incidence. Other adjuvants that do induce CMI are much too toxic for use in humans and are being progressively restricted in animals. Lactoferrin is different from microbial adjuvants and from cytokine adjuvants; it is a natural effector molecule that directly participates in host defenses and in the induction of cell mediated immune responses. Phase I studies demonstrate that Lactoferrin as an adjuvant given with BCG enhances delayed type hypersensitivity (DTH) in mice in a dose dependent fashion with no apparent toxicity. Mechanistically, it induces IL-12 and TNF-alpha production by macrophages thereby generating a local environment likely to push immune responses towards development and maintenance of CMI. Our Phase I data indicates Lactoferrin augments BCG vaccination as demonstrated by increased lymphocytic proliferation, and IFN-gamma, IL-2 and IL-12(p40) production towards BCG antigens. Furthermore, aerosol challenge with virulent Mycobacterium tuberculosis (MTB) following Lactoferrin vaccination demonstrated reduction in organism dissemination to spleen, and markedly improved lung pathology that was comparable to Complete Freund's Adjuvant controls. Phase II will specifically address the utility and efficacy of a novel, fully humanized glycoform of recombinant Lactoferrin produced in Pichia pastoris as an adjuvant to augment efficacy of BCG vaccination to subsequent challenge with virulent MTB.

描述（由申请人提供）：该项目的总体目标是开发人重组乳铁蛋白作为卡介苗的佐剂，以增强细胞介导免疫（CMI）并保护结核分枝杆菌感染后的肺泡完整性。改进的无毒佐剂，特别是能够诱导CMI的佐剂，是免疫学研究和人畜疫苗开发所需要的。在开发抗结核病疫苗方面尤其如此，牛分枝杆菌卡介苗（卡介苗）作为一种疫苗未能有效地减少全球发病率。其他可诱导CMI的佐剂毒性太大，不能用于人类，并且正在逐步限制在动物中的应用。乳铁蛋白不同于微生物佐剂和细胞因子佐剂；它是一种天然的效应分子，直接参与宿主防御和诱导细胞介导的免疫反应。I期研究表明，乳铁蛋白作为佐剂与卡介苗一起给予，以剂量依赖的方式增强小鼠的延迟型超敏反应（DTH），无明显毒性。在机制上，它诱导巨噬细胞产生IL-12和tnf - α，从而产生一个可能推动免疫反应发展和维持CMI的局部环境。我们的I期数据表明，乳铁蛋白增强了卡介苗接种，其表现为淋巴细胞增殖增加，以及对卡介苗抗原产生ifn - γ、IL-2和IL-12（p40）。此外，乳铁蛋白疫苗接种后，毒力结核分枝杆菌（MTB）的气溶胶攻击显示生物体传播到脾脏的减少，并显着改善肺部病理，与完全弗氏佐剂对照组相当。II期研究将专门研究一种新型的、完全人源化的重组乳铁蛋白糖型的效用和有效性，该糖型由毕氏酵母生产，可作为辅助剂，增强卡介苗接种对随后的强毒性MTB的效力。