Counter Regulatory Receptors and Allergic Inflammation

哮喘是一种慢性炎症过程，其特征是驻留的肥大细胞激活，并渗入Th2细胞、嗜酸性粒细胞和中性粒细胞，从而导致呼吸道结构元素的变化。下调炎症反应的策略在哮喘的治疗中至关重要。本项目的目的是验证一种假设，即肥大细胞、嗜酸性粒细胞和中性粒细胞的激活可能受到白细胞免疫球蛋白样受体(LIRS)的调节，LIRS是一类与小鼠gp49同源的细胞表面受体，在细胞质区域具有基于免疫受体酪氨酸的抑制基序(ITIMs)。特异性目的1证实LIR-5在外周血中性粒细胞和嗜酸性粒细胞以及培养的成熟人肥大细胞中的表达，并确定其他LIR-5在这些细胞中的表达。特异性目的2研究LIR-5在肥大细胞和嗜酸性粒细胞中的抑制作用，并将在特异性目的1的基础上扩展到其他LIR的研究。由于LIR在炎症条件下调节表达的潜在重要性，以及作为一种调节效应细胞功能的治疗方法，特异性目的3将重点放在LIR在体外培养的脐血嗜酸细胞和肥大细胞中的发育调节，以及IL(IL)3、IL-5或GM-CSF处理外周血嗜酸细胞以抑制细胞凋亡和增加炎症介质产生的LIR的表达和功能。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，因为我们发现有证据表明，它们在这些过敏性炎症的关键效应细胞中表达。这些研究将揭示这一新的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。

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.