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

描述（由申请人提供）： 虽然经常被认为是一种儿童疾病，但过敏性哮喘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和免疫系统之间的反复相互作用促进的，哮喘疾病的性质与老年人免疫功能的恶化相结合，导致随着年龄的增长诊断增加。此外，老年人的症状往往更严重，导致治疗选择较少，对当前治疗干预的反应较差。我们实验室的最新结果表明，环境暴露于内毒素和通过吸入细菌内毒素（脂多糖-LPS）后在肺中形成髓源性抑制细胞（MDSC）建立对过敏原的耐受性之间存在联系。这一发现是卫生假说的潜在机制，卫生假说于1989年提出，指出暴露于病原体相关产物（如内毒素）可能对未来的过敏反应具有保护作用。内毒素和抑制细胞形成之间的联系对我们理解肺功能有着巨大的意义。重要的是，我们已经能够在过敏性炎症模型中治疗性地使用这些抑制细胞（MDSC）。由于MDSC可以通过GM-CSF和LPS的组合在体外产生，因此在逐个患者的基础上进行治疗性干预具有巨大的潜力，从而进一步研究这些细胞的产生和功能。 公共卫生相关性： 1989年首次提出的卫生假说表明，在生命早期暴露于细菌衍生的产物（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的潜在机制。在遇到细菌内毒素后，在肺中观察到频率增加的抑制性骨髓细胞群。这些骨髓细胞能够以治疗的方式抑制过敏性炎症，从而进一步研究该细胞群的形成和功能。

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.