Mechanisms of phagocytic cell defects induced by inhibitory IgG

抑制性IgG诱导吞噬细胞缺陷的机制

• 批准号: 8751338
• 负责人: Daniel G. Remick
• 金额: $ 24.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751338
• 关键词: Accounting; Aliquot; Animals; Antibodies; Antigens; Autoantibodies; Bacteria; Binding; Biological Assay; Caring; Cell physiology; Colony-forming units; Data; Defect; Depressed mood; Disease; Effectiveness; Elements; Enhancing Antibodies; Enteral; Epitopes; Fc Receptor; Grant; Growth; Heterogeneity; Human; Immune response; Immunoglobulin G; Immunoglobulins; Individual; Investigation; Life; Ligation; Literature; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Modeling; Morbidity - disease rate; Mus; Nature; Outcome; Pathway interactions; Patients; Phagocytes; Plasma; Production; Publishing; Puncture procedure; Reporting; Risk; Role; Sampling; Sepsis; System; Testing; Therapeutic; Therapeutic Intervention; Time; cancer cell; cytokine; improved; insight; killings; macrophage; mortality; novel; novel therapeutics; pathogen; prevent; public health relevance; receptor; research study; response; septic; tumor

DESCRIPTION (provided by applicant): Sepsis continues to cause significant morbidity and mortality and there is an unmet medical need to improve the care of septic patients. Previous treatments have failed due to a lack of understanding of the basic immune response. While sepsis has a high mortality, there is a wide range in the pathophysiologic response to pathogens. Last year we published a novel observation that provides significant insight into the heterogeneity of the septic response using the murine model of sepsis induced by cecal ligation and puncture (CLP). Several days pior to the induction of sepsis there is a pre-existing factor within the plasma that significantly increases sepsis mortality. This factor functions by decreasing the clearance of bacteria from the septic host. Preliminary data suggest that this plasma factor is an inhibitory immunoglobulin G, iIgG. This application will test the hypothesis that mice which die from sepsis have a pre-existing inhibitory IgG which reduces phagocyte function, resulting in decreased bacterial killing and decreased survival after sepsis. The first specific aim will determine the nature of the molecule and verify that it is an IgG. Additional experiments will define what portion of the antibody is responsible for the decreased bacterial killing. Most studies examining antibodies test the Fab binding to bacterial epitopes. This aim examines the role of the Fc portion of the IgG in mediating the reduced bacterial killing. Previous cancer studies have shown that antibodies which clear cancer cells both recognize the cancer cells and bind to the appropriate Fc? receptors. The second specific aim will examine the mechanisms of how this inhibitory factor decreases killing of bacteria by phagocytic cells by focusing on the Fc? receptors and bacterial killing pathways. Successful completion of this grant will help to identify a potential new pathway that alters the response to sepsis. Specifically, an important element for survival from the septic insult may be determined by humoral factors present even before the onset of sepsis. Therapeutic interventions may involve a combination of blocking the inhibitory IgG and augmenting recruitment of new phagocytic cells to allow better eradication of the bacteria.

描述(由申请人提供)：脓毒症继续导致显著的发病率和死亡率，改善脓毒症患者护理的医疗需求尚未得到满足。由于缺乏对基本免疫反应的了解，以前的治疗都失败了。虽然脓毒症的死亡率很高，但对病原体的病理生理反应却有很大范围。去年，我们发表了一项新的观察，利用盲肠结扎和穿孔(CLP)诱导的小鼠脓毒症模型，对脓毒症反应的异质性提供了重要的见解。在脓毒症诱导的前几天，血浆中有一种预先存在的因子，它显着增加了脓毒症的死亡率。该因子通过减少细菌从败血症宿主中的清除而发挥作用。初步数据表明，该血浆因子是一种抑制性免疫球蛋白G，即IgG。这项应用将检验一种假设，即死于脓毒症的小鼠具有预先存在的抑制免疫球蛋白，这种免疫球蛋白会降低吞噬细胞功能，导致细菌杀灭减少，败血症后存活率降低。第一个特定的目的是确定分子的性质，并验证它是一种免疫球蛋白。更多的实验将确定抗体的哪一部分对细菌杀伤力的降低负责。大多数检测抗体的研究都是检测Fab与细菌表位的结合。这一目的是研究免疫球蛋白Fc部分在介导细菌杀灭减少中的作用。以前的癌症研究表明，清除癌细胞的抗体既能识别癌细胞，又能与适当的Fc结合？感受器。第二个具体目的是研究这种抑制因子如何通过聚焦于Fc来减少吞噬细胞对细菌的杀灭？受体和细菌杀死途径。这笔赠款的成功完成将有助于确定一种潜在的新途径，改变对脓毒症的反应。具体地说，败血症患者存活的一个重要因素可能是在脓毒症发生之前就已经存在的体液因素。治疗干预措施可能包括结合阻断抑制的免疫球蛋白和增加新的吞噬细胞的募集，以便更好地根除细菌。