Differential regulation of mast cell-mediated allergic responses by IL-10

项目摘要 该项目的重点是IL-10差异调节和促进的机制， 肥大细胞（MC）增生，异质性，激活和细胞功能在 IgE和非IgE介导的对食物抗原的过敏反应的发展。 我们已经证明了免疫调节细胞因子IL-10在驱动MC中的关键作用 食物过敏期间的扩张、激活和细胞因子产生。IL-10致敏的MC表现出 增强的增殖、IgE介导的被动过敏反应和TH 2型 细胞因子这表明IL-10在MC的稳态和功能中的新作用。然而，在这方面， IL-10促进MC活化的机制尚不十分清楚， 测定此外，IL-10对MC的这些促炎作用是否延伸至 具体MC谱系，在本质上是全球性的，还是依赖于上下文的，还有待研究。这 该项目结合了假设检验和有针对性的机械方法，以进一步探讨 IL-10调节MC功能的机制。这些包括了解IL-10是否 差异调节MC对不同抗原刺激的反应，评估其对 异质MC子集，并确定其影响是否受源控制 细胞类型。长期的总体目标是：1）通过以下方式识别细胞内在和外在因素： IL-10促进或抑制不同的MC群体并调节其效应子功能 在2型炎症反应期间;和2）检查全身和功能性局部组织 IL-10调节MC扩增和活化的结果。目标1将阐明 IL-10促进IgE介导的粘膜MC对生理食物抗原的应答， 花生和鸡蛋过敏原，并检查其对非IgE介导的过敏途径的影响， 致敏包括IL-33诱导的过敏反应。IL-10的作用是否也延伸到 将评估结缔组织MC，并将评估两者的表型和转录组学特征。 将映射MC子集。目的2将评估细胞内源性和旁分泌IL-10的作用。 10对MC增生和效应子功能的影响。目的3将确定来源依赖性IL-10的作用。 10，并确定TH 2或非TH 2衍生的IL-10是否可以差异调节MC功能。 考虑到IL-10在各种T和MC过程中的已知多效性病理和调节作用， 介导的免疫反应，包括抗寄生虫反应和过敏，并考虑其 作为一种典型的免疫调节细胞因子，重要的是要进一步确定其机制 IL-10的促炎作用及其促进而不是抑制 MC依赖性反应。因此，这些研究不仅与NIAID的使命有关， 而且还可以用于识别用于治疗干预的基于精确度的方法。

PROJECT SUMMARY This project focuses on the mechanisms by which IL-10 differentially regulates and promotes mast cell (MC) hyperplasia, heterogeneity, activation and cellular functions during the development of IgE and non-IgE-mediated allergic responses to food antigens. We have demonstrated a key role for the immunomodulatory cytokine IL-10 in driving MC expansion, activation, and cytokine production during food allergy. IL-10-primed MCs exhibited enhanced proliferation, IgE-mediated passive anaphylaxis, and the production of TH2-type cytokines. This suggests a novel role for IL-10 in the homeostasis and function of MCs. However, the mechanisms by which IL-10 promotes MC activation are not very clear and remain to be determined. Furthermore, whether these proinflammatory effects of IL-10 on MCs extend to specific MC lineages, are global in nature, or context-dependent also remain to be examined. This project combines hypothesis testing and targeted mechanistic approaches to further probe the mechanisms by which IL-10 regulates MC functions. These include understanding whether IL-10 differentially regulates MC responses to distinct antigenic stimuli, assessment of its effects on heterogeneous MC subsets, and determination of whether its effects are controlled by the source cell type. The long-term overall goals are to: 1) identify cell-intrinsic and extrinsic factors by which IL-10 promotes or suppresses distinct MC populations and regulates their effector function during type 2 inflammatory responses; and 2) examine the systemic and functional local tissue consequences of regulation of MC expansion and activation by IL-10. Aim 1 will elucidate whether IL-10 promotes IgE-mediated mucosal MC responses to physiological food antigens such as peanut and egg allergen and examine its effects on non-IgE-mediated pathways of allergic sensitization including IL-33-induced anaphylaxis. Whether the effects of IL-10 also extend to connective tissue MCs will be assessed and the phenotypic and transcriptomic profiles of both MC subsets will be mapped. Aim 2 will assess the contributions of cell-intrinsic and paracrine IL- 10 to MC hyperplasia and effector function. Aim 3 will identify the effects of source-dependent IL- 10 and determine whether TH2 or non-TH2-derived IL-10 can differentially regulate MC function. Given the known pleiotropic pathologic and regulatory effects of IL-10 during various T and MC- mediated immune responses including anti-parasitic responses and allergy, and considering its status as a canonical immunoregulatory cytokine, it is important to further identify the mechanisms underlying the proinflammatory effects of IL-10 and its ability to promote rather than suppress MC-dependent responses. As such, these studies are not only relevant to the mission of NIAID but may also serve to identify precision-based approaches for therapeutic interventions.