Role of ICOS-B7h Regulatory Costimulatory Pathway in Fetomaternal Tolerance

描述(申请人提供)：ICOS-B7h调节共刺激通路在母系耐受中的作用胎儿有父亲的抗原，可以激发强烈的同种异体T细胞反应。然而，一般来说，半异基因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，母体白细胞的凋亡在母体对异基因胎儿的耐受中起到了作用，这种细胞可以被胎儿抗原激活。通过调节性T细胞通路传递给激活的T细胞的负信号也是效应性T细胞扩张的天然抑制物。本课题组最近的研究表明，阴性T细胞共刺激通路PD-1-PDL1对维持母胎耐受至关重要。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。为了研究阻断或通过这一途径传递信号是否会改变妊娠结局，从而暗示在耐受性中的作用，我们利用了一个已建立的同种异体妊娠模型，在该模型中，CBA雌性与C57BL/6雄性交配。在该模型中，自发性吸收率约为20%。我们的初步结果表明，ICOS/B7h参与了母胎耐受，因为在体内阻断这一途径会导致自发吸收率增加(从正常配对的20%增加到抗B7h单抗治疗组的53%)。这种影响仅见于同种异体受孕，而不存在于同基因受孕。我们将继续研究ICOS-B7h通路在调节胎儿同种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特异性封闭抗体以及基因缺陷小鼠进一步阐明ICOS-B7h途径诱导母胎耐受的体内机制。 胎儿代表着母体免疫系统的外来实体，然而这种“天然”的同种异体移植通常不会被排斥。五十年前，它是由Medawar(Medawar，P.B.1953)提出的。交响乐。SoC。实验比奥尔。7：320-338)，怀孕期间应该有免疫耐受性，以防止针对胎儿表达的父系抗原的侵略性母体同种免疫反应。反复妊娠丢失影响了1%到3%的夫妇，其中大约一半的病例没有可识别的原因。此外，一些研究将一些妊娠并发症与异常的母体免疫反应联系起来。本课题组最近的研究表明，阴性T细胞共刺激通路PD-1-PDL1对维持母胎耐受至关重要。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。我们将利用ICOS和B7h特异性封闭抗体以及基因缺陷小鼠，研究具有免疫调节特性的共刺激分子ICOS-B7h在母胎耐受中的作用。了解母胎耐受的复杂机制对于开发新的策略以预防或减少高危人群的自然流产具有重要意义。

DESCRIPTION (provided by applicant): Role of ICOS-B7h Regulatory Costimulatory Pathway in Fetomaternal Tolerance 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 has demonstrated that negative T cell costimulatory pathway PD-1-PDL1 is critical for maintaining fetomaternal tolerance. 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 53% 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. 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 has demonstrated that negative T cell costimulatory pathway PD-1-PDL1 is critical for maintaining fetomaternal tolerance. 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.