Counter Regulatory Receptors and Allergic Inflammation

反调节受体和过敏性炎症

• 批准号: 6344610
• 负责人: Jonathan Peter Arm
• 金额: $ 20.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6344610
• 关键词: clinical research; colony stimulating factor; eosinophil; human subject; hypersensitivity; inflammation; interleukin 3; interleukin 5; laboratory mouse; laboratory rabbit; leukocyte activation /transformation; mast cell; neutrophil; receptor; receptor expression

Asthma is a chronic inflammatory process characterized by activation of resident mast cells and infiltrating Th2 cells, eosinophils, and neutrophils with consequent changes in the structural elements of the airways. Strategies to downregulate the inflammatory response are of critical importance in the management of asthma. The objective of this Project is to test the hypothesis that the activation of mast cells, eosinophils, and neutrophils may be modulated by the leukocyte immunoglobulin- like receptors (LIRs), a family of cell surface receptors that are homologous to mouse gp49 and that possess immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic domain. Specific Aim 1 is to confirm the expression of LIR-5 in peripheral blood neutrophils and eosinophils and in culture- derived mature human mast cells and to determine the expression of other LIRs in these cells. Specific Aim 2 investigates the inhibitory actions of LIR-5 in mast cells and eosinophils and will be extended to a study of other LIRs as based on the results of Specific Aim 1. Because of the potential importance of regulated expression of LIRs in inflammatory conditions and as a therapeutic approach to modulating effector cell function, Specific Aim 3 will focus on the developmental regulation of LIRs in eosinophils and mast cells derived by in vitro culture from cord blood, and the expression and function of LIRs in peripheral blood eosinophils treated with interleukin (IL) 3, IL-5, or GM- CSF to inhibit apoptosis and increase inflammatory mediator generation. Again, our focus will be on LIR-5 and will be extended to other members of the LIR family as we find evidence that they are expressed in these critical effector cells of allergic inflammation. These studies will reveal the potential of this novel family of molecules in regulating the allergic response and provide the impetus to pursue these molecules as novel therapeutic targets in the treatment of allergic disease and asthma.

哮喘是一种慢性炎症过程，其特征是常驻肥大细胞激活并浸润 Th2 细胞、嗜酸性粒细胞和中性粒细胞，从而导致气道结构要素发生变化。 下调炎症反应的策略对于哮喘的治疗至关重要。 本项目的目的是检验肥大细胞、嗜酸性粒细胞和中性粒细胞的激活可能受白细胞免疫球蛋白样受体 (LIR) 调节的假设，LIR 是与小鼠 gp49 同源的细胞表面受体家族，并且具有细胞质结构域中基于免疫受体酪氨酸的抑制基序（ITIM）。 具体目标 1 是确认外周血中性粒细胞和嗜酸性粒细胞以及培养物衍生的成熟人类肥大细胞中 LIR-5 的表达，并确定这些细胞中其他 LIR 的表达。 具体目标 2 研究 LIR-5 在肥大细胞和嗜酸性粒细胞中的抑制作用，并将根据具体目标 1 的结果扩展到其他 LIR 的研究。由于 LIR 的调节表达在炎症条件和中的潜在重要性，作为调节效应细胞功能的治疗方法，Specific Aim 3 将重点关注通过脐带血体外培养获得的嗜酸性粒细胞和肥大细胞中 LIR 的发育调节，以及用白细胞介素 (IL) 3、IL-5 或 GM-CSF 处理的外周血嗜酸性粒细胞中 LIR 的表达和功能，可抑制细胞凋亡并增加炎症介质的产生。 同样，我们的重点将放在 LIR-5 上，并将扩展到 LIR 家族的其他成员，因为我们发现证据表明它们在过敏性炎症的这些关键效应细胞中表达。 这些研究将揭示这一新型分子家族在调节过敏反应方面的潜力，并为将这些分子作为治疗过敏性疾病和哮喘的新治疗靶点提供动力。