Pregnancy-induced T cell exhaustion: an opportunity to reduce immunosuppression

妊娠引起的 T 细胞耗竭：减少免疫抑制的机会

• 批准号: 10374315
• 负责人: PAIGE M PORRETT
• 金额: $ 17.52万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374315
• 关键词: Adaptive Immune System; Adopted; Alloantigen; Alloimmunization; Antigens; B-Lymphocytes; CD28 gene; CD8-Positive T-Lymphocytes; Calcineurin; Calcineurin inhibitor; Caring; Cell Nucleus; Cells; Characteristics; Cyclosporine; Cytoplasm; Data; Dependence; Differentiation Antigens; Dose; Event; Evolution; Experimental Models; Female; Fetus; Functional disorder; Future; Genetic Transcription; Graft Survival; Immune; Immune response; Immune system; Immunize; Immunologic Memory; Immunologics; Immunosuppression; Impairment; Improve Access; Kidney; Kidney Transplantation; Knowledge; Laboratories; Life; Malignant Neoplasms; Mediating; Memory; Microchimerism; Mus; Nuclear Translocation; Organ Donor; Organ Transplantation; Outcome; Population; Predisposition; Pregnancy; Pregnancy Histories; Renal function; Signal Transduction; Source; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic immunosuppression; Tissues; Transplant Recipients; Transplantation; Woman; allograft rejection; chronic infection; embryo/fetus antigen; exhaust; exhaustion; experience; experimental study; fetal; gender disparity; improved; in vivo; insight; mouse model; negative affect; nephrotoxicity; parous; pre-clinical; prevent; programmed cell death protein 1; programs; receptor; response; transcription factor

PROJECT SUMMARY (ABSTRACT) Pregnancy is a common alloimmunizing event that impacts transplant access and outcomes among women. Although T cells of the maternal immune system are routinely activated by fetal alloantigen, it is unclear whether T cells stimulated by fetal antigen differentiate into canonical memory cells during pregnancy. The long-term fate and recall potential of these antigen-experienced T cells in the maternal repertoire are of particular importance to female transplant recipients, whose T cells may be capable of rapid rejection of a donor organ that shares tissue antigens with a prior pregnancy. Unfortunately, our poor understanding of T cell fate in women with a history of pregnancy has contributed to significant gender disparity in transplantation. Preliminary data in our mouse model suggest that fetal antigen during pregnancy promotes the differentiation of CD8+ T cells that persist in the maternal repertoire but have restricted functionality. While these T cells can still mediate rapid allograft rejection, they appear to be distinct from memory T cells that differentiate during other types of alloimmunization. Different populations of antigen-experienced T cells in alloimmunized transplant recipients may have unique requirements for immunosuppression. In this proposal, we will investigate how populations of antigen-experienced T cells induced by either pregnancy or transplantation differ from one another (Aim 1) and determine whether these differences promote immunosuppression reduction strategies in women (Aim 2). We anticipate that the knowledge generated by these studies will alter current immunosuppression strategies to improve the care of alloimmunized transplant recipients.

项目概要（摘要） 妊娠是一种常见的同种免疫事件，影响女性的移植机会和结果。 虽然母体免疫系统的T细胞通常被胎儿同种异体抗原激活，但目前还不清楚 胎儿抗原刺激的T细胞是否在妊娠期间分化为典型记忆细胞。的 这些抗原经历的T细胞在母体库中的长期命运和回忆潜力是 特别重要的是女性移植受者，其T细胞可能能够快速排斥一个 与先前怀孕共享组织抗原的捐赠器官。不幸的是，我们对T细胞的理解不足， 有怀孕史的妇女的命运导致了移植中的显著性别差异。 在我们的小鼠模型中的初步数据表明，妊娠期间的胎儿抗原促进分化， CD8+ T细胞持续存在于母体库中，但功能有限。虽然这些T细胞可以 它们仍然介导快速同种异体移植排斥，它们似乎与在移植过程中分化的记忆T细胞不同。 其他类型的同种异体免疫。同种异体免疫小鼠中不同群体的抗原经历T细胞 移植受者可能对免疫抑制有独特的要求。在本提案中，我们将 研究妊娠或移植如何诱导抗原感受性T细胞群 彼此不同（目的1），并确定这些差异是否促进免疫抑制 妇女的减少战略（目标2）。我们预计，这些研究产生的知识将改变 目前的免疫抑制策略，以改善同种免疫移植受体的护理。