Immunomodulation by Pregnancy Specific Glycoprotein 17

妊娠特异性糖蛋白 17 的免疫调节

• 批准号: 6982814
• 负责人: Gabriela S Dveksler
• 金额: $ 32.67万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6982814
• 关键词: Immunomodulation; Pregnancy; Specific; Glycoprotein; 17

DESCRIPTION (provided by applicant): The mechanisms responsible for the protection of the fetal semiallograft from attack by the matemal immune system are complex and remain incompletely understood. Establishment of a type-2 (TH2) immune response is believed to be one of the key factors responsible for pregnancy success as well as for the decreases in disease activity in pregnant women suffering from certain autoimmune diseases. Hormones and cytokines produced by the placenta have been implicated in the generation of the TH2 environment. Pregnancy specific glycoproteins (PSGs) are produced by the placenta and are secreted into the maternal circulation from the time of implantation. Neutralization of PSGs by Abs leads to spontaneous abortion and PSGs induce the secretion of anti-inflammatory cytokines. These findings suggest that PSGs may have an important role in regulation of the immune response during pregnancy. Our long-term goal is to define the roles and mechanisms of action of PSGs in normal and abnormal pregnancies. The central hypothesis of this application is that murine PSG17 contributes to the establishment of an immune environment favoring a TH2 immune response. The rationale behind the proposed research is that a better understanding of the role of PSGs in controlling immunity during pregnancy could result in the implementation of new therapies for women suffering of recurrent pregnancy losses and other immune-based pathologies. To accomplish the objectives of this application we will pursue three specific aims: (1) Determine whether PSG17-CD9 interactions provide a co-stimulatory signal that stimulates naive CD4 T cell differentiation to CD4 effector T helper cells. This will be accomplished by establishing whether binding of PSG17 to its receptor CD9 affects the proliferation of these cells and the cytokines they secrete. (2) Determine whether PSG17 binding to APC favors TH2 cell development before and after Ag encounter. For this purpose, we will evaluate the effects of PSG17 treatment of dendritic cells and the effects of PSG17 treatment in APC in their ability to induce differentiation of T cells derived from TcR transgenic mice upon primary and secondary stimulation. (3) Determine the nature of the in vivo response of non-pregnant PSG17-expressing mice to a parasite. Mice injected with PSG17 will be challenged with Trichuris muris and the cytokine expression in mesenteric lymph nodes, total serum Ig levels and worm burden will be analyzed.

描述（由申请人提供）：负责保护胎儿半乳肠移植免受马特马尔免疫系统攻击的机制是复杂的，并且尚不完全理解。据信，建立2型（TH2）免疫反应是导致妊娠成功的关键因素之一，以及患有某些自身免疫性疾病的孕妇疾病活动的减少。胎盘产生的激素和细胞因子与TH2环境的产生有关。胎盘特异性糖蛋白（PSG）由胎盘产生，并从植入时分泌到母体循环中。通过ABS对PSG进行中和导致自发流产，PSG诱导抗炎细胞因子的分泌。这些发现表明，PSG在怀孕期间的免疫反应调节中可能具有重要作用。我们的长期目标是定义PSG在正常和异常妊娠中的作用的作用和机制。该应用的核心假设是，鼠PSG17有助于建立有利于Th2免疫反应的免疫环境。拟议的研究背后的理由是，更好地了解PSG在控制怀孕期间的免疫力中的作用可能会导致针对患有复发性怀孕损失和其他免疫病理的妇女实施新的疗法。为了实现此应用程序的目标，我们将追求三个特定的目的：（1）确定PSG17-CD9相互作用是否提供了共刺激信号，该信号刺激了幼稚的CD4 T细胞分化与CD4效应T辅助细胞的分化。这将通过确定PSG17与其受体CD9的结合是否影响这些细胞的增殖和它们分泌的细胞因子的增殖来实现。 （2）确定PSG17与APC的结合是否有利于Ag相遇之前和之后的Th2细胞发育。为此，我们将评估PSG17对树突状细胞的治疗的影响，以及PSG17在APC中的影响在诱导TCR转基因小鼠对初级和二次刺激的TCR转基因小鼠衍生的T细胞分化的能力。 （3）确定非妊娠PSG17小鼠对寄生虫的体内反应的性质。注射PSG17的小鼠将受到trichuris muris的挑战，并且将分析肠系膜淋巴结中的细胞因子表达，总血清Ig水平和蠕虫负担。