Regulatory Costimulatory Pathways & Fetomaternal Tolerance

监管共刺激途径

• 批准号: 7879229
• 负责人: INDIRA GULERIA
• 金额: $ 38.26万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7879229
• 关键词: Affect; Alloantigen; Allogenic; Allografting; Antigen-Presenting Cells; Antigens; Apoptosis; Asthma; Autoimmunity; B-Lymphocytes; Binding; Blocking Antibodies; Bone Marrow; CD8-Positive T-Lymphocytes; CD80 gene; CD8B1 gene; Cell Death; Cells; Cessation of life; Chimeric Proteins; Complex; Conceptus; Couples; Data; Dendritic Cells; Development; Female; Fetal Resorption; Fetus; Genes; Goals; Grant; Hypersensitivity; ITGAX gene; Immune; Immune response; Immune system; Knowledge; Lead; Leukocytes; Ligands; Mediating; Modeling; Molecular; Monoclonal Antibodies; Mothers; Mus; Organ Transplantation; Partner in relationship; Pathway interactions; Peptide/MHC Complex; Placenta; Play; Populations at Risk; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy loss; Process; Property; Published Comment; Publishing; Recurrence; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Role; Signal Transduction; Spontaneous abortion; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Transplantation; Transplantation Tolerance; United States National Institutes of Health; Withdrawal; allograft rejection; anergy; base; cell mediated immune response; cell type; cytokine; embryo/fetus antigen; fetal; in vivo; in vivo Model; inhibitor/antagonist; knockout gene; male; mouse model; novel strategies; novel therapeutics; physiologic model; premature; prevent; public health relevance; receptor; response; tool

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.

描述（由申请方提供）：胎儿具有可引起强烈同种异体T细胞应答的父方抗原。然而，一般来说，半同种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。一些研究者已经证明，母体白细胞的凋亡（其可以响应于胎儿抗原而被激活）在母体对同种异体胎儿的耐受性中起作用。通过调节性T细胞途径递送至活化的T细胞的负信号也充当效应T细胞扩增的天然抑制剂。本课题组最近的研究表明，阴性T细胞共刺激通路PD-1-PDL 1对维持母胎耐受至关重要。PDL 1的阻断和缺乏导致胎儿吸收增加。由于PDL 1在各种细胞类型以及组织上表达，我们将通过各种分子方法研究这些细胞和组织在母胎界面赋予耐受性中的相对作用。ICOS-B7 h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B7 h在小鼠胎盘中的表达。为了研究通过该途径的阻断或信号传导是否会改变妊娠结局并因此表明在耐受性中的作用，我们利用了已建立的同种异体妊娠模型，其中CBA雌性与C57 BL/6雄性交配。该模型中的自发吸收率约为20%。我们的初步结果表明，ICOS/B7 h参与了胎母耐受，因为体内阻断该途径导致自发吸收率增加（从正常交配的约20%增加至抗B7 h mAb处理组的约46%）。这种效应仅见于同种异体而非同系孕体。我们将扩大我们的研究范围，探讨ICOS-B7 h通路在调节胎儿同种异体移植物接受或排斥过程中的功能和机制。我们将利用ICOS和B7 h特异性阻断抗体以及基因缺陷小鼠进一步阐明ICOS-B7 h通路诱导母胎耐受的体内机制。总的来说，这些研究将帮助我们了解负责在母胎界面的耐受性的分子机制，以及在理解移植耐受性在大。 公共卫生相关性：胎儿代表母体免疫系统的外来实体，但这种“天然”同种异体移植物通常不会被排斥。50年前，Medawar（Medawar，P.B. 1953. Symp. Soc. Exp. 7：320-338），在妊娠期间应存在免疫耐受性以保护免受针对胎儿表达的父本抗原的侵袭性母体同种免疫应答。复发性流产影响所有夫妇的1%至3%，其中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-PDL 1对维持母胎耐受至关重要。我们将利用各种转基因小鼠研究该途径在母胎界面赋予耐受性的机制。ICOS-B7 h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B7 h在小鼠胎盘中的表达。我们将利用ICOS和B7 h特异性阻断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-B7 h在母胎耐受中的作用。了解复杂的机制，母胎耐受性有重要意义的发展新的战略，以防止或减少自然流产的高危人群，特别是在一般有更好的移植耐受性。