Regulatory Costimulatory Pathways & Fetomaternal Tolerance

描述（由申请人提供）：胎儿具有父亲抗原，可引起强烈的同种异体T细胞反应。然而，一般来说，半异体胎儿通常不会被排斥，这表明存在防止排斥的主动耐受机制。一些研究人员已经证明，母体白细胞的凋亡可能在胎儿抗原反应中被激活，在母体对异体胎儿的耐受中起作用。通过调节性T细胞途径传递给活化T细胞的负信号也作为效应T细胞扩增的天然抑制剂。我们小组最近的研究表明，负T细胞共刺激通路PD-1-PDL1对维持母婴耐受性至关重要。阻断和缺乏PDL1导致胎儿吸收增加。由于PDL1在各种细胞类型和组织中表达，我们将通过各种分子方法研究这些细胞和组织在胎母界面赋予耐受性方面的相对作用。ICOS-B7h是另一种具有免疫调节特性的共刺激分子。我们已经能够显示B7h在小鼠胎盘中的表达。为了研究该通路的阻断或信号传导是否会改变妊娠结局，从而提示其在耐受性中的作用，我们使用了一个已建立的同种异体妊娠模型，其中CBA雌性与C57BL/6雄性交配。该模型的自发吸收率约为20%。我们的初步结果表明，ICOS/B7h参与了胎儿耐受，体内阻断该途径导致自发吸收率增加（从正常交配的约20%增加到抗B7h单抗处理组的约46%）。这种效应只存在于异基因概念中，而不存在于同基因概念中。我们将进一步研究ICOS- B7h通路在调节胎儿异体移植接受或排斥过程中的功能和机制。我们将利用ICOS和B7h特异性阻断抗体以及基因缺陷小鼠进一步描述ICOS-B7h途径诱导胎母耐受的体内机制。总的来说，这些研究将帮助我们了解在母胎界面耐受的分子机制，以及从整体上理解移植耐受。

DESCRIPTION (provided by applicant): The fetus has paternal antigens which can evoke strong allogeneic T cell responses. However, in general the semi-allogeneic fetus is not usually rejected indicating the existence of active tolerance mechanisms that prevent rejection. It has been demonstrated by several investigators that apoptosis of maternal leukocytes, which could get activated in response to fetal antigens, plays a role in maternal tolerance to an allogeneic fetus. Negative signals delivered to activated T cells by regulatory T cell pathways also act as natural inhibitors for effector T cell expansion. Recent studies from our group have demonstrated that negative T cell costimulatory pathway PD-1-PDL1 is critical for maintaining fetomaternal tolerance. Blockade as well as deficiency of PDL1 resulted in increased fetal resorption. Since PDL1 is expressed on various cell types as well as tissues, we will through various molecular approaches study the relative role of these cells and tissues in conferring tolerance at the fetomaternal interface. ICOS-B7h is another costimulatory molecule with immunoregulatory properties. We have been able to show the expression of B7h in the placentae of mice. In order to study if blockade or signaling through this pathway alters pregnancy outcomes and hence suggest a role in tolerance, we utilized an established model of allogeneic pregnancy in which CBA females are mated with C57BL/6 males. The spontaneous rate of resorption in this model is approximately 20%. Our preliminary results show that ICOS/B7h is involved in fetomaternal tolerance as in vivo blockade of this pathway resulted in increase in rate of spontaneous resorption (from ~20% in normal matings to ~46% in the anti-B7h mAb treated group). This effect was seen only in allogeneic but not in syngeneic concepti. We will extend our studies to investigate the functions and mechanisms of the ICOS- B7h pathway in regulating the process of fetal allograft acceptance or rejection. We will further delineate the in vivo mechanisms involved in ICOS-B7h pathway induced fetomaternal tolerance utilizing ICOS and B7h specific blocking antibodies as well as gene deficient mice. Overall these studies will help us understand the molecular mechanisms responsible for tolerance at the fetomaternal interface as well as in understanding transplantation tolerance at large. PUBLIC HEALTH RELEVANCE: The fetus represents a foreign entity to the maternal immune system, yet this "natural" allograft is not normally rejected. Fifty years ago, it was proposed by Medawar (Medawar, P.B. 1953. Symp. Soc. Exp. Biol. 7:320-338) that immunological tolerance should be present during pregnancy to protect against an aggressive maternal alloimmune response directed at the paternal antigens expressed by the fetus. Recurrent pregnancy loss affects 1% to 3% of all couples, and about half of these cases have no identifiable cause. Furthermore, a number of studies associate some pregnancy complications with abnormal maternal immune responses. Recent studies from our group have demonstrated that negative T cell costimulatory pathway PD-1-PDL1 is critical for maintaining fetomaternal tolerance. We will study the mechanism by which this pathway confers tolerance at the fetomaternal interface by utilizing various transgenic mice. ICOS-B7h is another costimulatory molecule with immunoregulatory properties. We have been able to show the expression of B7h in the placentae of mice. We will study the role of ICOS-B7h, costimulatory molecule with immunoregulatory properties in fetomaternal tolerance utilizing ICOS and B7h specific blocking antibodies as well as gene deficient mice. Understanding the complex mechanisms of fetomaternal tolerance has important implications for developing novel strategies to prevent or reduce spontaneous abortion in at-risk populations in particular and in general to have better transplant tolerance.