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: 7339658
• 负责人: MANIKKAM SUTHANTHIRAN
• 金额: $ 54.18万
• 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/7339658
• 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-6; Investigation; Kidney; Kidney Transplantation; Laboratories; Lead; Link; Measures; Messenger RNA; Methodology; Modeling; Mus; Organ Transplantation; Outcome; Play; Polymerase Chain Reaction; 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.

总体目标是为人类同种异体结果提供有关人类同种异体结果的信息。 CD4+ CD25+ T淋巴细胞的专门子集，T调节细胞对于抑制至关重要 自身免疫和保持自我耐受性。 T调节细胞表达FOXP，而非冗余 该规范因素对免疫稳态的贡献生动证明了 人类的致命多核炎症性疾病在FOXPS基因中具有功能丧失突变。 我们建议测试MRNA水平的FOXP和mRNA水平的假设 链接的FOXP调节基因网络可预测：（a）移植后同种异体移植功能，（b）急性 排斥的严重程度和结果，以及（c）慢性同种异体移植肾病。具体目的是： 特定目的1：检验狐狸调节网络基因的mRNA水平的假设， 在急性拒绝的发作中测量：（a）预测急性拒绝严重程度； （b） 预测急性排斥的结果。尿液和外周血将在 来自NIH赞助的合作临床的肾脏同种异体移植受者的诊断同种异体移植活检 移植试验（CTOT）。尿细胞和外周血细胞mRNA水平和FOXP的水平 mrnas fortgf-betal，IL-10，IL-2，CD25，CD4，CDS，CD27，Interferon-Gamma，IL-6，IL-6，TNF-Alpha，CD80， CD86，CD28，CTLA-4，TLR-4和TLR-8将使用前放大辅助实时测量 定量PCR分析，并研究了其与急性拒绝严重性和可逆性的关联。 特定目的2：测试foxps调节网络基因的mRNA水平预测的假设 肾脏同种异体移植功能和慢性同种异体肾病的发育。顺序尿液和 将从参与CTOT研究的肾脏同种异体移植接受者那里收集外周血标本 FOXPS调节网络基因的FOXP和mRNA水平的mRNA水平（在SA1下列出）将 对其预测（a）移植功能的能力进行测量和研究 同种异体肾病。 我们的研究通过研究临床上重要结果的鲁棒细胞机制，可能会导致 同种异体接受者的个性化治疗方法并为疗法提供信息，包括考虑Treg 细胞管理同种异体移植受者。