Immunomodulation by Pregnancy Specific Glycoprotein 17

妊娠特异性糖蛋白 17 的免疫调节

• 批准号: 6580154
• 负责人: Gabriela S Dveksler
• 金额: $ 33.46万
• 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/6580154
• 关键词: T lymphocyte; antigen presenting cell; cell differentiation; cellular immunity; dendritic cells; enzyme linked immunosorbent assay; genetically modified animals; glycoproteins; helper T lymphocyte; laboratory mouse; parasitism; pregnancy; pregnancy immunology; receptor binding; tissue /cell culture

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）：保护胎儿半同种异体移植物免受母体免疫系统攻击的机制很复杂，仍然不完全清楚。2型（TH 2）免疫应答的建立被认为是导致妊娠成功以及患有某些自身免疫性疾病的孕妇的疾病活动减少的关键因素之一。胎盘产生的激素和细胞因子与TH 2环境的产生有关。妊娠特异性糖蛋白（PSG）由胎盘产生，并从着床时分泌到母体循环中。Abs中和PSG导致自然流产，PSG诱导抗炎细胞因子的分泌。这些发现表明，PSG可能在妊娠期间的免疫反应的调节中发挥重要作用。我们的长期目标是确定PSG在正常和异常妊娠中的作用和作用机制。本申请的中心假设是鼠PSG 17有助于建立有利于TH 2免疫应答的免疫环境。拟议研究背后的基本原理是，更好地了解PSG在控制妊娠期间免疫力方面的作用，可能会导致对患有复发性妊娠丢失和其他免疫性疾病的妇女实施新的治疗方法。（1）确定PSG 17-CD 9相互作用是否提供刺激初始CD 4 T细胞分化为CD 4效应T辅助细胞的共刺激信号。这将通过确定PSG 17与其受体CD 9的结合是否影响这些细胞的增殖及其分泌的细胞因子来实现。(2)确定PSG 17与APC结合是否有利于抗原接触前后的TH 2细胞发育。为此，我们将评估树突状细胞的PSG 17处理的效果和APC中的PSG 17处理在它们诱导源自TcR转基因小鼠的T细胞在初次和二次刺激后分化的能力方面的效果。(3)确定非妊娠PSG 17表达小鼠对寄生虫的体内反应性质。将用鼠鞭虫攻击注射PSG 17的小鼠，并分析肠系膜淋巴结中的细胞因子表达、总血清IG水平和蠕虫负荷。