Immunomodulatory B7 Family Proteins in the Placenta

描述（由申请人提供）：胎盘免疫耐受功能的破坏可能导致胎盘不能充分保护胎儿免受母体免疫系统可能产生的有害影响。这反过来又可能导致胎盘的某些病理，如宫内生长迟缓和先兆子痫，这些并发症不仅危及母亲的健康，而且可能对孩子的健康产生长期影响。最近的研究揭示了多种属于B7和CD28家族的细胞表面相关蛋白的存在，这些蛋白在免疫耐受中起着至关重要的作用。我们的初步研究表明，这些分子是胎儿滋养细胞调节母体免疫系统的强有力的候选者。在本提案的AIM 1中，我们将绘制(a) B7家族配体B7- dc和B7- h2以及(b)它们的CD28受体PD-1和ICOS在人母胎界面的细胞来源。胎盘组织和母胎界面细胞亚群将使用分子和组织学技术检测B7和CD28家族成员的表达。在AIM 2中，我们将阐明滋养细胞中BT-H1和BT-H2的调控机制。这一目标将确定这些分子被调控的分子和细胞机制。AIM 3将确定B7-H1和B7-H2对淋巴细胞死亡、增殖和细胞因子产生的功能影响。在这些研究中，人类滋养细胞培养模型将用于剖析滋养细胞B7-H1和B7-H2向淋巴细胞传递信号的分子和细胞后果。最后，AIM 4将评估B7-H1和B7-H2信号通路中断对妊娠小鼠细胞因子产生、白细胞浸润和胎儿生存能力的影响。为此，植入后妊娠小鼠将接受中和抗体治疗，并对这些生殖参数进行评估。这些研究有望对尽管母亲和胎儿之间存在同种异体不相容，但成功怀孕的机制产生丰富的见解。此外，这些研究将提高我们在开发治疗不孕症和其他疾病（如癌症和自身免疫性疾病）方面的知识。

DESCRIPTION (provided by applicant): A breakdown in the immunotolerogenic function of the placenta may result in a failure of the placenta to adequately protect the fetus against possible harmful effects of the maternal immune system. This could in turn contribute to certain pathologies of the placenta such as intrauterine growth retardation and preeclampsia, complications that not only put the mother' s health at risk, but also may have long-term effects on the health of the child. Recent studies have unveiled the existence of multiple cell surface-associated proteins belonging to the B7 and CD28 families that are of fundamental importance in immunological tolerance. Our preliminary studies have shown that these molecules are strong candidates for modulation of the maternal immune system by fetal trophoblast cells. In AIM 1 of this proposal, we will map the cellular sources of (a) the B7 family ligands, B7-DC and B7-H2, and (b) their CD28 receptors, PD-1 and ICOS, at the human maternal-fetal interface. Placental tissues and subpopulations of cells of the maternal-fetal interface will be examined for B7 and CD28 family member expression using molecular and histological techniques. In AIM 2, we will elucidate the mechanisms of regulation of BT-H1 and BT-H2 in trophoblast cells. This aim will determine the molecular and cellular mechanisms by which these molecules are regulated. AIM 3 will be to determine the functional effects of B7-H1 and B7-H2 on lymphocyte death, proliferation, and cytokine production. In these studies, human trophoblast cell culture models will be used to dissect the molecular and cellular consequences of signaling from trophoblast B7-H1 and B7-H2 to lymphocytes. Lastly, AIM 4 will evaluate the consequences of disruption of B7-H1 and B7-H2 signaling on cytokine production, leukocyte infiltration, and fetal viability in pregnant mice. In this aim, post-implantation pregnant mice will be treated with neutralizing antibodies and will be evaluated for these reproductive parameters. These studies are expected to yield a wealth of insight on the mechanisms by which successful pregnancy is permitted despite the allogeneic incompatibility between mother and fetus. Further, these studies will advance our knowledge in developing therapies for infertility and a wide range of other ailments such as cancer and autoimmune disease.