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: 8070416
• 负责人: Stephanie L. Poe
• 金额: $ 2.58万
• 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/8070416
• 关键词: Address; Age; Allergens; Allergic Disease; Allergic inflammation; Animals; Antigens; Appearance; Asthma; Bone Marrow; Breathing; Cell physiology; Cell secretion; Cells; Childhood; Childhood Asthma; Chronic; Coculture Techniques; Data; Detection; Deterioration; Developed Countries; Development; Diagnosis; Disease; Dose; Elderly; Endotoxins; Environmental Exposure; Exposure to; Extrinsic asthma; Frequencies; Future; Gene Silencing; Generations; Genetic; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; House Dust Mite Allergens; Hygiene; Immune system; Immunity; Immunosuppression; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-17; Interleukin-6; Investigation; Laboratories; Life; Ligands; Light; Link; Lipopolysaccharides; Lung; Malignant Neoplasms; Manuscripts; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; NF-kappa B; Nature; Nitric Oxide; Pathway interactions; Patients; Phenotype; Play; Population; Prevalence; Production; Property; Role; STAT5A gene; Signal Pathway; Signal Transduction; Signaling Molecule; Small Interfering RNA; Stem cells; Suppressor-Effector T-Lymphocytes; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Time; Transgenic Organisms; Work; aging population; allergic response; base; bone; cytokine; early childhood; immune function; in vivo; monocyte; pathogen; pulmonary function; response; toll-like receptor 4; tumor growth

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.

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。