Cytokine regulation of human basophil responses

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引起的疾病是一个日益严重的公共卫生问题。过敏性炎症与辅助性T细胞2 (Th2) CD4+ T细胞有关，这些细胞产生Th2细胞因子，包括白细胞介素-4 （IL-4）和IL-13。虽然Th2 CD4+ T细胞在过敏反应中的作用得到了很好的认识，但启动和调节过敏性炎症的先天细胞类型和细胞因子仍然不清楚。最近的研究表明，嗜碱性细胞是一种促进Th2细胞因子反应的先天细胞。此外，细胞因子胸腺基质淋巴生成素（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表明，TSLP引发了一种独特的小鼠嗜碱性粒细胞群体，这些嗜碱性粒细胞对Th2相关的细胞因子IL-33有反应。其他数据表明，活化的人嗜碱性细胞表达TSLP受体（TSLPR），并且从嗜酸性食管炎（EoE）患者中分离的嗜碱性细胞更可能表达IL-33R。综上所述，这些数据表明TSLP可能调节影响过敏性炎症的人类嗜碱性粒细胞反应。本提案中概述的具体目标将直接测试TSLP对人类嗜碱性粒细胞群体的影响。目的1将利用人源化小鼠模型，在该模型中，人类嗜碱性细胞可以很容易地定义，以评估体外和体内暴露于TSLP后的人类嗜碱性细胞表型和功能。此外，一种新的小鼠食物过敏模型将用于研究TSLP对人源化小鼠肠道变应性炎症发展过程中人类嗜碱性粒细胞数量的影响。Aim 2中描述的研究将评估人类EoE患者和健康对照组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。最后，将评估TSLP基因发生功能获得或功能丧失突变的患者的嗜碱性粒细胞反应，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，来研究控制人类过敏性炎症的先天机制。

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.