Mechanisms of phagocytic cell defects induced by inhibitory IgG

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，并且在改善脓毒症患者的护理方面存在未满足的医疗需求。由于缺乏对基本免疫反应的了解，以前的治疗都失败了。虽然败血症死亡率高，但对病原体的病理生理反应范围广泛。去年，我们发表了一项新的观察结果，通过使用盲肠结扎和穿刺（CLP）诱导的脓毒症小鼠模型，对脓毒症反应的异质性提供了重要的见解。在脓毒症发生前几天，血浆中存在一种预先存在的因素，可显著增加脓毒症的死亡率。这个因子的作用是减少从败血性宿主清除细菌。初步资料表明，该血浆因子是一种抑制性免疫球蛋白G （iIgG）。该应用程序将验证一种假设，即死于败血症的小鼠具有预先存在的抑制IgG，该IgG会降低吞噬细胞功能，导致败血症后细菌杀灭量减少，存活率降低。第一个特定目标将确定分子的性质并验证它是IgG。额外的实验将确定抗体的哪一部分负责降低细菌杀灭。大多数检测抗体的研究都是检测Fab与细菌表位的结合。本目的目的是研究IgG的Fc部分在介导细菌杀伤减少中的作用。先前的癌症研究表明，清除癌细胞的抗体既能识别癌细胞，又能与合适的Fc？受体。第二个具体目标是通过聚焦Fc？受体和细菌杀灭途径。这项资助的成功完成将有助于确定一种改变对败血症反应的潜在新途径。具体来说，脓毒症患者存活的一个重要因素可能是由脓毒症发病前的体液因素决定的。治疗干预可能包括阻断抑制IgG和增加新吞噬细胞募集的组合，以便更好地根除细菌。

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.