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: 7919727
• 负责人: MANIKKAM SUTHANTHIRAN
• 金额: $ 53.59万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919727
• 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.

总体目标是开发人类同种异体移植物结局的免疫生物标志物。 调节性T细胞是CD 4 + CD 25 + T淋巴细胞的一个特殊亚群，对于抑制T淋巴细胞增殖至关重要。 自身免疫和维持自身耐受性。调节性T细胞表达FoxpS，而非冗余的 这一特化因子对免疫稳态的贡献通过以下事件的发生生动地证明： 人类致命性多灶性炎症性疾病，FoxpS基因功能缺失突变。 我们建议测试FoxpS mRNA水平和FoxpS mRNA水平的假设， 连锁FoxpS调控基因网络预测：（a）移植后同种异体移植物功能，（B）急性 排斥严重程度和结果，和（c）慢性同种异体移植物肾病。具体目标是： 具体目的1：为了检验FoxpS调控网络基因的mRNA水平， 在急性排斥发作期间测量：（a）预测急性排斥严重性;和（B） 明确急性排斥反应的结局。将在以下时间采集尿液和外周血： 来自两个NIH赞助的合作临床研究中心的肾移植受者的诊断性移植物活检 移植试验（CTOT）。尿细胞和外周血细胞FoxpS的mRNA水平以及 TGF-β 1、IL-10、IL-2、CD 25、CD 4、CDS、CD 27、干扰素-γ、IL-6、TNF-α、CD 80、 将使用预扩增辅助实时荧光定量分析仪测量CD 86、CD 28、CTLA-4、TLR-4和TLR-8。 定量PCR分析，并研究其与急性排斥反应的严重程度和可逆性的相关性。 具体目的2：检验FoxpS调控网络基因的mRNA水平预测 移植肾功能和慢性移植肾肾病的发展。连续尿液和 将从CTOT研究中入组的肾移植受者中采集外周血标本 并且FoxpS的mRNA水平和FoxpS调控网络基因的mRNA水平（列于SA 1下）将 测量和研究它们预测（a）移植物功能和（B）慢性炎症发展的能力。 同种异体移植肾病 我们的研究，通过调查一个强大的细胞机制的临床重要成果，可能会导致 同种异体移植受者个体化治疗和包括Treg输注在内的信息治疗 细胞来管理同种异体移植受体。