FoxP3 Regulatory Network mRNA Profiles and Human Renal Transplant Outcomes

总体目标是开发免疫生物标记物，为人类同种异体移植的结果提供信息。 作为CD4+CD25+T淋巴细胞的一个特殊亚群，T调节细胞对抑制 自身免疫和保持自我容忍。T调节细胞表达FoxpS，非冗余 这一特定因子对免疫动态平衡的贡献通过一种 带有FoxpS基因功能缺失突变的人类致命性多灶性炎症性疾病。 我们建议检验以下假设：FoxpS的mRNAs水平和FoxpS的mRNAs水平 连锁的FoxpS调控基因网络可预测：(A)移植后功能，(B)急性 排斥的严重程度和结局，以及(C)慢性同种异体移植肾病。具体目标是： 具体目的1：验证FoxpS调控网络基因的mRNA水平， 在急性排斥发作期间测量：(A)预测急性排斥严重程度；和(B) 预测急性排斥反应的结局。尿液和外周血液将在一年内采集 在NIH赞助的两个合作临床中登记的肾移植受者的诊断性同种异体肾活检 移植试验(CTOT)。尿细胞和外周血细胞FoxpS基因表达水平及血清FoxpS水平 转化生长因子-β1、IL-10、IL-2、CD25、CD4、CDS、CD27、干扰素-γ、IL-6、肿瘤坏死因子-α、CD80、 CD86、CD28、CTLA-4、TLR-4和TLR-8将使用预扩增辅助实时测量 定量聚合酶链式反应分析，并研究它们与急性排斥反应严重程度和可逆性的关系。 特定目标2：检验FoxpS调控网络基因的mRNA水平预测的假说 移植肾功能与慢性移植物肾病的发展。顺序性尿和 将采集参加CTOT研究的肾移植受者的外周血液样本。 以及FoxpS的mRNA水平和FoxpS调控网络基因的mRNA水平(在SA1下列出)将 被测量和调查他们预测(A)移植物功能和(B)慢性 同种移植物肾病。 我们的研究，通过研究临床上重要结果的强大的细胞机制，可能导致 同种异体移植受者的个体化治疗和告知治疗，包括考虑输注Treg 用于管理同种异体移植受者的细胞。

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.