Decidual Cell/Placental Interactions

描述(申请人提供)：在正常妊娠中，母亲的免疫系统被编程为体液免疫优先于细胞免疫的情况。尽管许多研究已经解决了细胞介导的胎盘及其膜的破坏如何保护细胞毒细胞的问题，但对抗体产生偏好背后的机制(S)的研究很少。最近，我们发现了一个可能的高抗体产生的外植体。在研究人胎盘非凋亡诱导肿瘤坏死家族配体/受体的合成时，我们了解到B淋巴细胞存活的促进剂BAFF和与BAFF相同的受体结合的APRIL在人胎盘中转录和翻译。因此，这两种配体可能会影响抗体的产生。在这项研究中，我们提出了三个具体目标。目的1是定义BAFF和APRIL在特定的人胎盘细胞亚群中的产生，并确定控制转录和翻译的条件。我们对两种细胞因子(干扰素7和IL-10)特别感兴趣，即缺氧和可溶性人类白细胞抗原-G，并提供了一些初步证据，支持这些与早孕和先兆子痫有关的分子可能是BAFF和/或APRIL基因表达的调节因子。在目的2中，我们建议研究基因缺失/过表达对小鼠妊娠的影响。我们的初步研究表明，BAFF和APRIL在小鼠胎盘中都有表达，并且有转基因和基因敲除模型可用。AIM 3旨在确定小鼠、健康妇女和患有自身免疫性疾病的妇女的血清BAFF和APRIL水平与怀孕之间的关系。对怀孕前和怀孕期间健康女性的研究将与芝加哥大学的C.Ober合作进行评估。咨询公司J.L.Nelson和J.Buyon将收集患有自身免疫性疾病的女性的类似血清。这些患者将根据疾病进行分层，并分析他们的血清中BAFF和APRIL的水平。我们期待这些研究为怀孕如何进行提供新的见解，而不损害孕妇对病原体的防御，为患有潜在自身免疫性疾病的母亲提供重要的新信息，并最终导致新的治疗方式。

DESCRIPTION (provided by applicant): In normal pregnancy the mother's immune system is programmed into a profile where humoral immunity is preferred to cell-mediated immunity. Studies on mechanism(s) underlying the preference for antibody production are very few in number although many investigations have addressed the question of how cell-mediated destruction of the placenta and its membranes might be protected from cytotoxic cells. Recently, we uncovered a likely explantation for high antibody production. When investigating synthesis of non-apoptosis-inducing Tumor Necrosis Family ligands/receptors in human placentas, we learned that BAFF, a promoter of B lymphocyte survival, and APRIL, which binds to the same receptors as BAFF but whose mode of action is not well understood, are transcribed and translated in human placentas. Thus, these two ligands may effect the deviation toward production of antibodies. In this study, we propose three Specific Aims. Aim 1 is to define production of BAFF and APRIL in specific subpopulations of human placental cells and identify conditions controlling transcription and translation. We are particularly interested in two cytokines (IFN 7 and IL-10), hypoxia and soluble HLA-G, and provide some preliminary evidence in support of idea that these molecules, which are associated with early pregnancy and preeclampsia, may be modulators of BAFF and/or APRIL gene expression. In Aim 2 we propose to investigate the effects of gene deletion/overexpression on pregnancy in mice. Our preliminary studies show that both BAFF and APRIL are expressed in mouse placentas, and both transgenic and knockout models are available. Aim 3 is designed to identify relationships between pregnancy and serum levels of BAFF and APRIL in mice, healthy women and women with autioimmune disease. The studies on healthy women prior to and during pregnancy will be assessed in collaboration with C. Ober, University of Chicago. Similar sets of sera from women with autoimmune disorders will be collected by Consultants J. L. Nelson and J. Buyon. The patients will be stratified by disorder and their sera analyzed for levels of BAFF and APRIL. We expect these studies to provide new insights into how pregnancy proceeds without compromising maternal defense against pathogens, to provide important new information on mothers with underlying autoimmune disease, and, ultimately, to lead toward new treatment modalities.