Role of Anti-GM-CSF Antibodies in Myeloid Cell Function & Innate Immunity

抗 GM-CSF 抗体在骨髓细胞功能中的作用

• 批准号: 7264359
• 负责人: Bruce C Trapnell
• 金额: $ 37.5万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7264359
• 关键词: A Mouse; Accounting; Address; Adhesions; Alveolar; Alveolar Macrophages; Antibodies; Autoimmune Process; Binding; Biochemical; Biological; Biological Assay; Catabolism; Cell physiology; Clinical; Count; Data; Development; Differentiation Antigens; Disease; Functional disorder; Granulocyte-Macrophage Colony-Stimulating Factor; Health; Hematopoiesis; Hematopoietic; Homeostasis; Human; Immune; Individual; Infection; Inflammatory; Kinetics; Knock-out; Laboratories; Lung; Macaca fascicularis; Mediating; Modeling; Mus; Myeloid Cells; Natural Immunity; Pathogenesis; Patients; Phagocytosis; Pharmacodynamics; Physiological; Play; Pulmonary Alveolar Proteinosis; Reporting; Research Personnel; Resolution; Respiratory Burst; Respiratory Failure; Risk; Role; Serum; Signal Transduction; Systemic infection; Testing; Time; Wild Type Mouse; antimicrobial; attributable mortality; base; immune function; in vivo; interest; killings; macrophage; microbial; monocyte; mortality; neutrophil; nonhuman primate; novel; programs; proto-oncogene protein Spi-1; receptor; surfactant; therapy design

DESCRIPTION (provided by applicant): Primary pulmonary alveolar proteinosis (PAP) is characterized by progressive accumulation of surfactant in the lungs resulting in respiratory failure as well as increased pulmonary and systemic infections that account for 18% of attributable mortality. Abrogation of GM-CSF signaling appears to be central to disease pathogenesis because GM-CSF knockout (GM-/-) mice develop PAP and have increased mortality from infection and because PAP in humans is associated with high levels of neutralizing anti-GM-CSF antibodies. We reported that GM-CSF is required to stimulate the terminal differentiation of alveolar macrophages (AMs) in mice and likely also in humans, and does so primarily via the hematopoietic transcription factor, PU.1. Neutrophil and monocyte counts are normal in PAP patients and GM-/- mice, suggesting GM-CSF has a critical role in the lung but not in hematopoiesis. Our Preliminary Data now show that low levels of anti-GM-CSF antibodies are present in disease-free, healthy individuals, and correlate inversely with neutrophil function; and that neutrophils are functionally impaired in both GMA/A mice and PAP patients. This proposal seeks to test the following general hypothesis: GM-CSF has a critical systemic role in innate immunity, stimulating mechanisms in myeloid cells determining basal levels of antimicrobial and other functions. Specifically, we hypothesize that (1) high levels of anti-GM-CSF antibodies are the cause of the clinical manifestations in PAP and not an epiphenomenon or a consequence of intercurrent microbial infection; and (2) low levels of anti-GM-CSF antibodies may play an important physiological role by binding and inactivating circulating GM-CSF, thereby modulating the basal immune responsiveness of myeloid cells. In Aim 1, we will determine the mechanism(s) by which anti-GM-CSF antibodies regulate functions in myeloid cells, including AMs, monocytes and neutrophils. In Aim 2, PAP will be recapitulated in healthy subjects by transfer of anti-GM-CSF antibodies from PAP patients into non-human primates, satisfying Koch's 2nd & 3rd postulates. In Aim 3, we will utilize a novel immune model of PAP in mice to determine the critical threshold level of anti-GM-CSF antibodies that abrogate GM-CSF bioactivity in vivo and determine the kinetics and pharmacodynamics of myeloid cell dysfunction and onset and resolution of PAP. Expected results will establish that anti-GM-CSF antibodies cause the clinical manifestations in PAP patients, and will determine underlying mechanisms of myeloid cell dysfunction. Results have biological implications for the role of GM-CSF in mucosal barrier function beyond PAP in both health and disease. Clinical implications exist for PAP therapies, and also for anti-GM-CSF antibody-based therapies to treat serious inflammatory disorders, an approach for which significant commercial interest and development have now emerged.

描述（由申请人提供）：原发性肺泡蛋白沉积症 (PAP) 的特征是肺部表面活性物质逐渐积累，导致呼吸衰竭以及肺部和全身感染增加，占死亡率的 18%。 GM-CSF 信号传导的消除似乎是疾病发病机制的核心，因为 GM-CSF 敲除 (GM-/-) 小鼠会出现 PAP 并增加感染死亡率，而且因为人类中的 PAP 与高水平的中和性抗 GM-CSF 有关。抗体。我们报道说，GM-CSF 是刺激小鼠肺泡巨噬细胞 (AM) 终末分化所必需的，也可能在人类中，并且主要通过造血转录因子 PU.1 来实现这一目的。 PAP 患者和 GM-/- 小鼠的中性粒细胞和单核细胞计数正常，表明 GM-CSF 在肺中发挥关键作用，但在造血中则不然。我们的初步数据现在表明，无病健康个体中存在低水平的抗 GM-CSF 抗体，并且与中性粒细胞功能呈负相关； GMA/A 小鼠和 PAP 患者的中性粒细胞功能均受损。该提案旨在检验以下一般假设：GM-CSF 在先天免疫中具有关键的系统作用，刺激骨髓细胞的机制，决定抗菌和其他功能的基础水平。具体而言，我们假设（1）高水平的抗 GM-CSF 抗体是 PAP 临床表现的原因，而不是并发微生物感染的附带现象或结果； (2)低水平的抗GM-CSF抗体可能通过结合和灭活循环GM-CSF而发挥重要的生理作用，从而调节骨髓细胞的基础免疫反应性。在目标 1 中，我们将确定抗 GM-CSF 抗体调节骨髓细胞（包括 AM、单核细胞和中性粒细胞）功能的机制。在目标 2 中，通过将 PAP 患者的抗 GM-CSF 抗体转移到非人类灵长类动物体内，将在健康受试者中重现 PAP，满足科赫的第二和第三假设。在目标 3 中，我们将利用小鼠 PAP 的新型免疫模型来确定抗 GM-CSF 抗体的临界阈值水平，从而消除体内 GM-CSF 的生物活性，并确定骨髓细胞功能障碍的动力学和药效学以及发病和缓解人民行动党。预期结果将确定抗 GM-CSF 抗体导致 PAP 患者的临床表现，并将确定骨髓细胞功能障碍的潜在机制。结果对于 GM-CSF 在健康和疾病中 PAP 以外的粘膜屏障功能中的作用具有生物学意义。对于 PAP 疗法以及基于抗 GM-CSF 抗体的治疗严重炎症性疾病的疗法存在临床意义，这种方法现已出现了重大的商业兴趣和开发。