P4-IVIG immunotherapy for adjunct treatment of severe respiratory infection

P4-IVIG 免疫疗法辅助治疗严重呼吸道感染

• 批准号: MR/M024970/1
• 负责人: Stephen Gordon
• 金额: $ 76.43万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM024970%2F1
• 关键词: P4; IVIG; immunotherapy; adjunct; treatment

Community-acquired pneumonia (CAP) is the commonest cause of infection-related death in the UK and accounts for 6% of admissions to Intensive Care. Patients with CAP who require Intensive Care still have a hospital mortality of 49.4%, despite antibiotics and optimal supportive care. Steroids and some immune-modifying treatments have been investigated as additional treatment in severe infection, but evidence for any survival benefit is heavily disputed. New therapies are needed to improve outcome, particularly as the Department of Health has highlighted the urgent threat of antibiotic resistant infections in the UK. This proposal investigates a strategy to stimulate immune responses both in the lung and the blood in patients with severe pneumonia by improving phagocyte (white blood cells that ingest and kill bacteria) function in the presence of antibody binding to the infecting bacteria.Pneumococcal surface adhesin A (PsaA) is a surface molecule of Streptococcus pneumoniae with a vital role in bacterial adherence. P4 is a 28-amino acid peptide fragment of PsaA which activates human phagocytes (both macrophages and neutrophils) resulting in adherence and internalization of pneumococci, staphylococci and gram negative bacteria in laboratory experiments. Furthermore, P4 administered with intravenous immunoglobulin (IVIG) as a source of anti-bacterial antibody increases uptake and killing of pneumococci by human lung macrophages, together with dramatically improving survival in animal models of pneumonia and infection by significantly reducing or clearing bacteria in both lungs and blood.This partnership aims to develop Augmented Passive Immunotherapy (API) trials to improve patient survival in the ITU, particularly from severe pneumonia. In this specific project, we will take the next step by synthesising a small quantity of P4, screening this for toxicity and checking that it works in established laboratory assays. Our immediate follow-on priority will be phase 1 study with both P4 and the P4/IVIG combination.

社区获得性肺炎（CAP）是英国感染相关死亡的最常见原因，占重症监护入院人数的6%。需要重症监护的CAP患者尽管使用抗生素和最佳支持治疗，但住院死亡率仍为49.4%。类固醇和一些免疫修饰治疗已被研究作为严重感染的额外治疗，但任何生存益处的证据都存在很大争议。需要新的疗法来改善结果，特别是因为卫生部强调了英国抗生素耐药性感染的紧迫威胁。本研究旨在探讨一种策略，通过改善吞噬细胞（摄取和杀死细菌的白色血细胞）在抗体结合感染细菌的情况下的功能，刺激严重肺炎患者肺部和血液中的免疫应答。肺炎球菌表面粘附素A（PsaA）是肺炎链球菌的表面分子，在细菌粘附中起重要作用。P4是PsaA的28个氨基酸的肽片段，其活化人吞噬细胞（巨噬细胞和嗜中性粒细胞两者），导致实验室实验中肺炎球菌、葡萄球菌和革兰氏阴性细菌的粘附和内化。此外，P4与静脉注射免疫球蛋白（IVIG）一起作为抗菌抗体的来源，增加了人肺巨噬细胞对肺炎球菌的摄取和杀伤，同时通过显着减少或清除肺部和血液中的细菌，显着提高了肺炎和感染动物模型的存活率。特别是严重的肺炎。在这个特定的项目中，我们将采取下一步，合成少量的P4，筛选其毒性，并检查它在已建立的实验室测定中是否有效。我们的直接后续优先事项将是P4和P4/IVIG组合的I期研究。