FoxP3 Regulatory Network mRNA Profiles and Human Renal Transplant Outcomes

描述（由申请方提供）：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信息。调节性T细胞是CD 4 + CD 25 + T淋巴细胞的一个特殊亚群，对抑制自身免疫和维持自身耐受至关重要。调节性T细胞表达Foxp 3，这种特异性因子对免疫稳态的非冗余贡献通过Foxp 3基因功能丧失突变的人类致命性多灶性炎症性疾病的发生生动地证明。我们建议检验以下假设：Foxp 3的mRNA水平和Foxp 3调控基因网络的mRNA水平可预测：（a）移植后同种异体移植物功能，（B）急性排斥反应的严重程度和结果，以及（c）慢性同种异体移植物肾病。具体目标是：具体目标1：为了检验以下假设：在急性排斥反应发作期间测量Foxp 3调控网络基因的mRNA水平：（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。在诊断性移植物活检时，将从入组两项NIH申办的移植合作临床试验（CTOT）的肾移植受者中采集尿液和外周血。尿细胞和外周血细胞Foxp 3 mRNA水平和TGF-β mRNA水平。1、IL-10、IL-2、CD 25、CD 4、CDS、CD 27、干扰素-γ、IL-6、TNF-α、CD 80、CD 86、CD 28、CTLA-4、TLR-4和TLR-8，并研究其与急性排斥严重程度和可逆性的相关性。具体目标二：探讨Foxp 3调控网络基因mRNA水平预测移植肾功能和慢性移植肾肾病发生的假设。将从CTOT研究中招募的肾移植受者中连续收集尿液和外周血标本，并测量Foxp 3的mRNA水平和Foxp 3调控网络基因的mRNA水平（列于SA 1下），并研究其预测（a）移植物功能和（B）慢性移植物肾病发展的能力。我们的研究，通过调查一个强大的细胞机制的临床重要的结果，可能会导致个体化治疗的同种异体移植受体和通知治疗，包括考虑输注Treg细胞来管理同种异体移植受体。

DESCRIPTION (provided by applicant): 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 Foxp3, 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 Foxp3 gene. We propose to test the hypotheses that levels of mRNA for Foxp3 and levels of mRNAs for a mechanistically linked Foxp3 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 Foxp3 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 Foxp3 and levels of mRNAs for TGF-?1, 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 Foxp3 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 Foxp3 and mRNA levels of Foxp3 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.