Human CTL-Mediated Injury of Graft Endothelial Cells

人 CTL 介导的移植物内皮细胞损伤

• 批准号: 7642483
• 负责人: JORDAN S POBER
• 金额: $ 43.37万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-10 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642483
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Adoptive Transfer; Affect; Allogenic; Allografting; Arteries; Attention; Biological Markers; Biopsy Specimen; CD8B1 gene; Calcineurin inhibitor; Caspase; Cathepsins; Cell Adhesion Molecules; Cells; Cessation of life; Clinical; Complement; Cytolysis; Cytoplasmic Granules; Data; Dominant-Negative Mutation; Effector Cell; Endothelial Cells; Erythropoietin; Exocytosis; Family member; Fluorescence; Funding; Generations; Genes; Granzyme; Human; IL2RA gene; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Injury; Interleukin-11; Investigation; Leukocytes; Mediating; Mediator of activation protein; Mitochondria; Modeling; Modification; Molecular; Mus; Organ Transplantation; Pathway interactions; Patients; Phenotype; Play; Population; Process; Proteins; RNA Interference; Research Personnel; Resistance; Role; Signal Transduction; Skin; Skin graft; Solid; T-Lymphocyte; Testing; Tissues; Transduction Gene; Transplant Recipients; Transplantation; Umbilical vein; base; cell injury; cell type; cytokine; genetic manipulation; genetic regulatory protein; human tissue; in vivo; killings; kinase inhibitor; mouse model; novel; novel diagnostics; overexpression; peripheral blood; pre-clinical; receptor; response; skin allograft; survivin

DESCRIPTION (provided by applicant): Cytolytic T lymphocytes (CTL) are major effectors of clinical allograft rejection in patients treated with calcineurin inhibitor-based immunosuppression and graft endothelial cells (EC) are major targets of CTL-mediated injury. Moreover, some CTL recovered from rejecting allografts are specific for EC and not other graft, cell types suggesting that such CTL arise in response to stimulation by graft EC. The investigators believe that improvements in post-transplant therapy should target those mechanisms least well controlled by current therapy, ie., CTL-mediated EC injury by either EC-selective or conventional MHC-restricted CTL, and that such improvements will depend on better understanding these mechanisms. This proposal (1) will investigate mechanisms utilized by EC to influence CTL maturation as well as the effects of modifying human EC, e.g., by cytokine treatments or gene transduction, on this process; will examine the role of adhesion molecules in the molecular basis of EC-selectivity; will compare the effects of adoptive transfer of EC-selective vs. conventional CTL in our huPBL-SCID/bg mouse models of allograft rejection; and will compare the phenotypes of EC-selective vs. conventional CTL using microarrays to develop biomarkers in order to identify EC-selective CTL in rejecting tissues generated both in huPBL-SCID/bg mouse models of allograft injury and in clinical biopsy specimens; (2) will determine the death pathways activated within human EC in response to EC-selective and to conventional CTL in culture and in biopsy specimens and identify strategies to block these responses; and (3) will investigate the mechanisms by which treatment with IL-11 or erythropoietin protect EC from CTL, paying particular attention to the role of STATS signaling. We will use microarrays to identify novel protective molecules. These data will provide a rational basis for developing new, complementary strategies to further reduce the incidence and consequences of allograft rejection.

描述(申请人提供)：细胞溶解T淋巴细胞(CTL)是临床同种异体移植排斥反应的主要效应者，在接受基于钙调神经磷酸酶抑制剂的免疫抑制治疗的患者中，移植物内皮细胞(EC)是CTL介导的损伤的主要靶点。此外，从排斥同种异体移植中恢复的一些CTL是EC特异性的，而不是其他移植物，这表明这种CTL是在移植物EC的刺激下产生的。研究人员认为，移植后治疗的改进应针对那些目前治疗控制最不好的机制，即EC选择性或传统MHC限制的CTL介导的EC损伤，这些改进将取决于对这些机制的更好理解。这项建议(1)将研究EC影响CTL成熟的机制以及通过细胞因子治疗或基因转导修饰人EC对这一过程的影响；将检查黏附分子在EC选择性的分子基础中的作用；将在我们的同种异体排斥反应的huPBL-SCID/BG小鼠模型中比较EC选择性与常规CTL过继转移的效果；并将利用微阵列技术比较EC选择性CTL表型与常规CTL表型，以确定EC选择性CTL在同种异体移植损伤huPBL-SCID/BG小鼠模型和临床活组织标本中产生的排斥反应；(2)确定培养和活组织标本中EC选择性CTL和常规CTL激活的死亡途径，并确定阻断这些反应的策略；(3)研究IL-11或促红细胞生成素处理EC免受CTL影响的机制，特别注意STATS信号转导系统的作用。我们将使用微阵列来识别新的保护性分子。这些数据将为开发新的补充策略以进一步减少同种异体移植排斥反应的发生率和后果提供合理的基础。