Immunomodulation by Pregnancy Specific Glycoprotein 17

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是复杂的，尚未完全了解。2型（TH2）免疫反应的建立被认为是怀孕成功的关键因素之一，也是患有某些自身免疫性疾病的孕妇疾病活动性降低的关键因素之一。胎盘产生的激素和细胞因子与TH2环境的产生有关。妊娠特异性糖蛋白（psg）由胎盘产生，从着床时起就分泌到母体循环中。抗体中和psg导致自然流产，psg诱导抗炎细胞因子的分泌。这些发现提示psg可能在妊娠期免疫反应的调节中起重要作用。我们的长期目标是明确psg在正常和异常妊娠中的作用和作用机制。该应用的中心假设是小鼠PSG17有助于建立有利于TH2免疫应答的免疫环境。这项拟议研究背后的基本原理是，更好地了解妊娠期间psg在控制免疫方面的作用，可能会导致对患有复发性妊娠丢失和其他免疫疾病的妇女实施新的治疗方法。为了实现这一应用的目标，我们将追求三个具体目标：(1)确定PSG17-CD9相互作用是否提供了一个共同刺激信号，刺激初始CD4 T细胞分化为CD4效应T辅助细胞。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及其分泌的细胞因子来实现。(2)确定PSG17与APC结合是否有利于Ag相遇前后TH2细胞的发育。为此，我们将评估PSG17处理树突状细胞的效果，以及PSG17处理APC在一次和二次刺激下诱导来自TcR转基因小鼠的T细胞分化的能力。(3)确定未怀孕表达psg17的小鼠体内对寄生虫的反应性质。注射PSG17的小鼠用鼠毛虫攻毒，分析肠系膜淋巴结细胞因子表达、血清总Ig水平和虫负荷。

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.