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发展人类重组乳铁蛋白作为BCG的辅助物，以增强细胞介导的免疫力（CMI）并在感染结核分枝杆菌感染后保护肺泡完整性。需要改进的无毒佐剂，尤其是能够诱导CMI的辅助药，以进行免疫学研究以及人类和兽医疫苗的开发。对于打击结核病的开发尤其如此，在这种情况下，作为疫苗的巴奇氏菌（BCG）菌株（BCG）菌株的功效未能使全球发病率降低。确实诱导CMI的其他佐剂过于毒性，无法在人类中使用，并且在动物中逐渐受到限制。乳铁蛋白不同于微生物佐剂和细胞因子佐剂。它是一种天然效应子分子，直接参与宿主防御和诱导细胞介导的免疫反应。第一阶段的研究表明，乳铁蛋白作为BCG辅助蛋白会以剂量依赖性的方式增强小鼠延迟类型的超敏反应（DTH），没有明显的毒性。从机械上讲，它通过巨噬细胞诱导IL-12和TNF-Alpha产生，从而产生了可能将免疫反应推向CMI的开发和维持的局部环境。我们的I期数据表明，乳铁蛋白增强了BCG疫苗接种，如淋巴细胞增殖的增加所证明，IFN-GAMMA，IL-2和IL-2和IL-12（p40）对BCG抗原的产生。此外，乳铁蛋白疫苗接种后对毒性分枝杆菌（MTB）造成的气溶胶挑战表明，生物体传播到脾脏的降低，并且显着改善了肺病理学，这与完整的弗洛伦德辅助对照相当。第二阶段将特别介绍一种新型的，完全人源化的糖型的疗效和在Pichia pastoris中产生的重组乳铁蛋白的糖化型，作为增强BCG疫苗接种疗效的辅助性，以随后对有毒MTB的挑战。