FoxP3 Regulatory Network mRNA Profiles and Human Renal Transplant Outcomes

FoxP3 调控网络 mRNA 谱和人肾移植结果

• 批准号: 7539927
• 负责人: MANIKKAM SUTHANTHIRAN
• 金额: $ 55.81万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7539927
• 关键词: Acute; Allografting; Autoimmunity; Biological Assay; Biological Markers; Biopsy; Blood Cells; Blood specimen; CD28 gene; CD80 gene; Cells; Chronic rejection of renal transplant; Clinical Trials; Creatinine; Data; Development; Diagnostic; Disease; Enrollment; Genes; Homeostasis; Human; IL2RA gene; Immune; Inflammatory; Infusion procedures; Interferon Type II; Interleukin-10; Interleukin-2; Interleukin-6; Investigation; Kidney; Kidney Transplantation; Laboratories; Lead; Link; Measures; Messenger RNA; Methodology; Modeling; Mus; Organ Transplantation; Outcome; Play; Regulator Genes; Regulatory T-Lymphocyte; Risk; Role; Self Tolerance; Sensitivity and Specificity; Serum; Severities; T-Lymphocyte; Testing; Time; Transcription Factor 3; Transplantation; Tumor Necrosis Factor-alpha; Urine; Winged Helix; graft failure; graft function; human TGFB1 protein; human TNF protein; kidney allograft; loss of function mutation; peripheral blood; pre-clinical; urinary

The overall objective is to develop immune biomarkers informative of human allograft outcomes. A specialized subset of CD4+CD25+ T lymphocytes, T regulatory cells is critical for suppressing autoimmunity and maintaining self-tolerance. T regulatory cells express FoxpS, and the non-redundant contribution of this specification factor to immune homeostasis is vividly demonstrated by the occurrence of a fatal multi-focal inflammatory disease in humans with a loss-of-function mutation in the FoxpS gene. We propose to test the hypotheses that levels of mRNA for FoxpS and levels of mRNAs for a mechanistically linked FoxpS regulatory gene network are predictive of: (a) post-transplant allograft function, (b) acute rejection severity and outcome, and (c) chronic allograft nephropathy. The Specific Aims are: Specific Aim 1: To test the hypothesis that mRNA levels of FoxpS regulatory network genes, measured during an episode of acute rejection: (a) predict acute rejection severity; and (b) prognosticate the outcome of acute rejection. Urine and peripheral blood will be collected at the time of a diagnostic allograft biopsy from renal allograft recipients enrolled in two NIH-sponsored Cooperative Clinical Trials of Transplantation (CTOT). Urinary cell and peripheral blood cell mRNA levels of FoxpS and levels of mRNAs forTGF-betal, IL-10, IL-2, CD25, CD4, CDS, CD27, interferon-gamma, IL-6, TNF-alpha, CD80, CD86, CD28, CTLA-4, TLR-4, and TLR-8 will be measured using a pre-amplification assisted real-time quantitative PCR assay, and investigated for their association with acute rejection severity and reversibility. Specific Aim 2: To test the hypotheses that mRNA levels of FoxpS regulatory network genes predict renal allograft function and development of chronic allograft nephropathy. Sequential urine and peripheral blood specimens will be collected from the renal allograft recipients enrolled in the CTOT studies and the mRNA levels of FoxpS and mRNA levels of FoxpS regulatory network genes (listed under SA1) will be measured and investigated for their ability to predict (a) graft function and (b) the development of chronic allograft nephropathy. Our study, by investigating a robust cellular mechanism for the clinically important outcomes, may lead to individualized treatment of allograft recipients and inform therapy including consideration of infusion of Treg cells to manage allograft recipients.

总体目标是开发可提供人类同种异体移植结果信息的免疫生物标志物。 T 调节细胞是 CD4+CD25+ T 淋巴细胞的特殊亚群，对于抑制 自身免疫和维持自我耐受。 T 调节细胞表达 FoxpS，并且非冗余 这种规范因素对免疫稳态的贡献通过以下现象的发生生动地证明了： 具有 FoxpS 基因功能丧失突变的人类致命性多灶性炎症性疾病。 我们建议测试 FoxpS 的 mRNA 水平和机制上的 mRNA 水平的假设 连接的 FoxpS 调控基因网络可预测：(a) 移植后同种异体移植功能，(b) 急性 排斥反应的严重程度和结果，以及 (c) 慢性同种异体移植肾病。具体目标是： 具体目标 1：检验 FoxpS 调控网络基因的 mRNA 水平的假设， 在急性排斥反应期间测量： (a) 预测急性排斥反应的严重程度； (b) 预测急性排斥反应的结果。尿液和外周血将在检查时收集 对参加两项 NIH 赞助的合作临床的肾同种异体移植受者进行诊断性同种异体移植活检 移植试验（CTOT）。尿细胞和外周血细胞中 FoxpS 的 mRNA 水平以及 TGF-β、IL-10、IL-2、CD25、CD4、CDS、CD27、干扰素-γ、IL-6、TNF-α、CD80 的 mRNA CD86、CD28、CTLA-4、TLR-4 和 TLR-8 将使用预放大辅助实时测量 定量 PCR 测定，并研究其与急性排斥严重程度和可逆性的关联。 具体目标 2：检验 FoxpS 调控网络基因的 mRNA 水平预测的假设 同种异体移植肾功能和慢性同种异体移植肾病的发展。连续尿液和 外周血标本将从参加 CTOT 研究的同种异体肾移植受者身上采集 FoxpS 的 mRNA 水平和 FoxpS 调控网络基因（在 SA1 下列出）的 mRNA 水平将 测量和研究其预测 (a) 移植物功能和 (b) 慢性疾病发展的能力 同种异体移植肾病。 我们的研究通过调查临床重要结果的强大细胞机制，可能会导致 同种异体移植受者的个体化治疗和信息治疗，包括考虑输注 Treg 细胞来管理同种异体移植受者。