Cross-talk Between GM-CSF and LPS/TLR4 in the Generation of MDSC-like Cells

GM-CSF 和 LPS/TLR4 在 MDSC 样细胞生成中的串扰

• 批准号: 7904681
• 负责人: Stephanie L. Poe
• 金额: $ 2.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904681
• 关键词: Age; Allergens; Allergic inflammation; Breathing; Cell physiology; Cells; Childhood; Chronic; Deterioration; Diagnosis; Disease; Elderly; Endotoxins; Environmental Exposure; Exposure to; Extrinsic asthma; Frequencies; Future; Generations; Granulocyte-Macrophage Colony-Stimulating Factor; Hygiene; Immune system; In Vitro; Inflammatory; Investigation; Laboratories; Life; Link; Lipopolysaccharides; Lung; Modeling; Myelogenous; Myeloid Cells; Nature; Patients; Population; Suppressor-Effector T-Lymphocytes; Symptoms; Therapeutic; Therapeutic Intervention; Work; aging population; allergic response; base; immune function; pathogen; public health relevance; pulmonary function; response

DESCRIPTION (provided by applicant): Although often thought of as a disease of childhood, allergic asthma is a chronic inflammatory condition of the lower airways that is frequently diagnosed later in life. Allergic asthma is promoted by repeated interactions between allergen(s) and the immune system and the nature of asthmatic disease combined with the deterioration of immune function in the elderly, results in increased diagnoses with age. Furthermore, symptoms are often worse in the aging population, resulting in fewer treatment options and poor response to current therapeutic interventions. Recent results from our laboratory suggest a connection between environmental exposure to endotoxin and the establishment of tolerance to allergens via the formation of myeloid-derived suppressor cells (MDSCs) in the lung following inhalation of bacterial endotoxin (lipopolysaccharide-LPS). This finding is a potential mechanism underlying the hygiene hypothesis, which was postulated in 1989, stating that exposure to pathogen-associated products, like endotoxin, may be protective against future allergic responses. This link between encounter with endotoxin and suppressor cell formation has huge implications for our understanding of pulmonary function. Importantly, we have been able to use these suppressor cells (MDSCs) therapeutically in a model of allergic inflammation. Because MDSCs can be generated in vitro by the combination of GM-CSF and LPS, there is great potential for therapeutic intervention on a patient-by-patient basis warranting further investigation of the generation and function of these cells. PUBLIC HEALTH RELEVANCE: The hygiene hypothesis, first postulated in 1989, suggests that exposure to bacterial-derived products like endotoxin very early in life, may contribute to tolerance to inhaled allergens. Recent work in our laboratory has found a potential mechanism underlying the hygiene hypothesis. A suppressive myeloid cell population has been observed in increased frequency in the lung after encounter with bacterial endotoxin. These myeloid cells are able to suppress allergic inflammation in a therapeutic manner warranting further investigation into the formation and function of this cell population.

描述(申请人提供)：虽然过敏性哮喘通常被认为是一种儿童疾病，但它是一种下呼吸道的慢性炎症性疾病，经常在以后的生活中被诊断出来。过敏性哮喘是由过敏原(S)和免疫系统之间的反复相互作用和哮喘疾病的性质加上老年人免疫功能的恶化而促进的，导致随着年龄的增长而增加诊断。此外，老龄化人口的症状往往更严重，导致治疗选择较少，对当前治疗干预措施的反应较差。我们实验室的最新结果表明，环境暴露内毒素与吸入细菌内毒素后肺内形成髓系抑制细胞(MDSCs)而建立对变应原的耐受性之间存在联系。这一发现是1989年提出的卫生学假说背后的一个潜在机制，该假说认为，接触与病原体相关的产品，如内毒素，可能会保护人们免受未来的过敏反应。遇到内毒素和抑制细胞形成之间的这种联系对于我们理解肺功能具有巨大的意义。重要的是，我们已经能够在过敏性炎症模型中使用这些抑制细胞(MDSCs)进行治疗。由于骨髓间充质干细胞可以通过GM-CSF和脂多糖的联合作用在体外产生，因此有很大的潜力对患者进行治疗干预，从而保证进一步研究这些细胞的生成和功能。 公共卫生相关性：1989年首次提出的卫生学假说表明，在生命早期接触细菌衍生产品，如内毒素，可能有助于对吸入性过敏原的耐受性。我们实验室最近的工作发现了卫生假说背后的一个潜在机制。在遇到细菌内毒素后，在肺中观察到抑制性髓系细胞群的频率增加。这些髓系细胞能够以一种治疗的方式抑制变态反应性炎症，这为进一步研究这类细胞的形成和功能奠定了基础。