Counter Regulatory Receptors and Allergic Inflammation

哮喘是一种慢性炎症过程，其特征是常驻肥大细胞的激活和Th2细胞、嗜酸性粒细胞和中性粒细胞的浸润，从而导致气道结构元素的改变。下调炎症反应的策略在哮喘治疗中至关重要。本项目的目的是验证肥大细胞、嗜酸性粒细胞和中性粒细胞的激活可能由白细胞免疫球蛋白样受体（LIRs）调节的假设，LIRs是一组细胞表面受体，与小鼠gp49同源，在细胞质域具有免疫受体酪氨酸基抑制基序（ITIMs）。特异性目的1是确认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LIR-5的表达，并确定这些细胞中其他lir的表达。Specific Aim 2研究了LIR-5在肥大细胞和嗜酸性粒细胞中的抑制作用，并将基于Specific Aim 1的结果扩展到其他lir的研究。由于LIRs在炎症条件下表达调控的潜在重要性，以及作为调节效应细胞功能的治疗方法，Specific Aim 3将重点关注LIRs在嗜酸性粒细胞和脐带血体外培养的肥大细胞中的发育调控，以及在白细胞介素（IL） 3、IL-5或GM- CSF处理的外周血嗜酸性粒细胞中LIRs的表达和功能，以抑制细胞凋亡和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，并为追求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.