Cytokine regulation of human basophil responses

人类嗜碱性粒细胞反应的细胞因子调节

• 批准号: 8255795
• 负责人: Elia D Tait Wojno
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255795
• 关键词: Address; Allergens; Allergic Disease; Allergic inflammation; American; Antigens; Asthma; Atopic Dermatitis; Basophilia; Basophils; Biological; Biology; CD4 Positive T Lymphocytes; Cells; Clinical; Collaborations; Data; Developed Countries; Development; Disease; Eosinophilic Esophagitis; Esophageal Tissue; Esophagus; Exhibits; Exposure to; Flow Cytometry; Food; Food Hypersensitivity; Genes; Genetic Polymorphism; Genotype; Growth Factor; Helminths; Heterogeneity; Histocompatibility Antigens Class II; Human; Hypersensitivity; Immune response; In Vitro; Inflammation; Interleukin-13; Interleukin-3; Interleukin-4; Interleukin-5; Interleukin-9; Intestines; Laboratories; Lead; Link; Mediating; Modeling; Morbidity - disease rate; Mus; Nature; Pathway interactions; Patients; Phenotype; Play; Population; Prevalence; Public Health; Receptor Gene; Receptor Signaling; Recombinants; Regulation; Reporting; Rhinitis; Role; Severity of illness; Signal Transduction; Site; Sorting - Cell Movement; Stimulus; T-Cell Development; TSLP gene; Testing; Therapeutic; Tissues; allergic response; base; cell type; cytokine; eosinophil; genome-wide; human TSLP protein; in vivo; in vivo Model; loss of function mutation; mast cell; mortality; mouse model; novel; novel strategies; peripheral blood; receptor; response

DESCRIPTION (provided by applicant): Allergic inflammation and resulting disease caused by inappropriate responses to food and environmental antigens is a growing public health issue. Allergic inflammation is associated with T helper 2 (Th2) CD4+ T cells that produce Th2 cytokines, including interleukin-4 (IL-4) and IL-13. While the role of Th2 CD4+ T cells is well recognized during allergic responses, the innate cell types and cytokines that initiate and regulate allergic inflammation remain poorly defined. Recent studies have implicated basophils as an innate cell that promotes Th2 cytokine responses. Additionally, the cytokine thymic stromal lymphopoietin (TSLP) has been associated with the development of allergic disease in mice and human patients. Preliminary data described in this proposal show that TSLP elicits a unique population of murine basophils that are responsive to the Th2- associated cytokine IL-33. Additional data demonstrate that activated human basophils express the TSLP receptor (TSLPR), and that basophils isolated from patients suffering from eosinophilic esophagitis (EoE) are more likely to express the IL-33R. Taken together, these data suggest that TSLP may regulate human basophil responses that influence allergic inflammation. The Specific Aims outlined in this proposal will directly test the influence of TSLP on human basophil populations. Aim 1 will utilize a humanized mouse model in which human basophils can be readily defined to assess human basophil phenotype and function following exposure to TSLP in vitro and in vivo. Additionally, a novel murine food allergy model will be used to investigate the effects of TSLP on human basophil populations in humanized mice during the development of allergic inflammation in the intestine. Studies described in Aim 2 will assess basophil phenotype and function in the peripheral blood and esophageal tissue of human EoE patients and healthy controls and basophil responsiveness to TSLP and IL-33 in vitro. Finally, basophil responses in patients that have a gain- or loss-of function mutation in the TSLP gene will be assessed and correlated to disease severity to determine whether TSLP genotype, basophil phenotype and function, and allergic disease state are associated. Collectively, these studies will utilize novel models and approaches, in conjunction with cutting-edge studies in human patients, to investigate the innate mechanisms that control allergic inflammation in humans. PUBLIC HEALTH RELEVANCE: Asthma and allergic diseases cause significant morbidity and mortality in industrialized nations, with more than 50% of people in the US suffering from at least one allergic disease. As the prevalence of allergic diseases continues to grow, there is a need to better understand the biological mechanisms that lead to allergic inflammation, in order to develop therapeutics and management strategies. This proposal will investigate the specific immunological pathways that underlie allergic disease in human patients.

描述（由申请人提供）：对食物和环境抗原的不适当反应引起的过敏性炎症和由此产生的疾病是一个日益严重的公共卫生问题。过敏性炎症与产生Th 2细胞因子（包括白细胞介素-4（IL-4）和IL-13）的辅助性T 2（Th 2）CD 4 + T细胞相关。虽然Th 2 CD 4 + T细胞在过敏反应中的作用得到了很好的认识，但引发和调节过敏性炎症的先天细胞类型和细胞因子仍然定义不清。最近的研究表明嗜碱性粒细胞是一种促进Th 2细胞因子应答的先天性细胞。此外，细胞因子胸腺基质淋巴细胞生成素（TSLP）与小鼠和人类患者过敏性疾病的发生有关。本提案中描述的初步数据显示，TSLP激发了对Th 2相关细胞因子IL-33有反应的鼠嗜碱性粒细胞的独特群体。另外的数据表明，活化的人嗜碱性粒细胞表达TSLP受体（TSLPR），并且从患有嗜酸性粒细胞性食管炎（EoE）的患者分离的嗜碱性粒细胞更可能表达IL-33 R。总之，这些数据表明，TSLP可能调节人类嗜碱性粒细胞的反应，影响过敏性炎症。本提案中概述的特定目的将直接检测TSLP对人嗜碱性粒细胞群体的影响。目的1将利用人源化小鼠模型，其中人嗜碱性粒细胞可以很容易地定义，以评估人嗜碱性粒细胞表型和功能后，暴露于TSLP在体外和体内。此外，一种新的鼠食物过敏模型将用于研究TSLP对人源化小鼠中的人嗜碱性粒细胞群体在肠中过敏性炎症发展期间的影响。目的2中描述的研究将评估人EoE患者和健康对照的外周血和食管组织中的嗜碱性粒细胞表型和功能，以及嗜碱性粒细胞对TSLP和IL-33的体外反应性。最后，将评估在TSLP基因中具有功能获得或丧失突变的患者中的嗜碱性粒细胞应答，并将其与疾病严重程度相关联，以确定TSLP基因型、嗜碱性粒细胞表型和功能以及过敏性疾病状态是否相关。总的来说，这些研究将利用新的模型和方法，结合人类患者的前沿研究，研究控制人类过敏性炎症的先天机制。 公共卫生相关性：哮喘和过敏性疾病在工业化国家中引起显著的发病率和死亡率，在美国超过50%的人患有至少10%的哮喘和过敏性疾病。 一种过敏性疾病随着过敏性疾病的流行持续增长，需要更好地了解导致过敏性炎症的生物学机制，以开发治疗和管理策略。该提案将调查人类患者过敏性疾病的特定免疫途径。