FoxP3 Regulatory Network mRNA Profiles and Human Renal Transplant Outcomes

描述（由申请人提供）：总体目标是开发人类同种异体移植结果的免疫生物标志物。作为CD4+CD25+ T淋巴细胞的一个特殊亚群，T调节细胞在抑制自身免疫和维持自身耐受性方面至关重要。T调节细胞表达Foxp3，而Foxp3基因功能缺失突变的致命性多灶性炎症的发生生动地证明了这一特定因子对免疫稳态的非冗余贡献。我们提出验证Foxp3 mRNA水平和Foxp3调控基因网络mRNA水平预测的假设：(a)移植后同种异体移植功能，(b)急性排斥反应严重程度和结果，以及(c)慢性同种异体移植肾病。具体目的是：具体目的1：验证在急性排斥反应发作期间测量Foxp3调控网络基因mRNA水平的假设：(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。在美国国立卫生研究院赞助的两项移植合作临床试验（CTOT）的肾移植受者进行诊断性异体移植活检时，将收集尿液和外周血。尿细胞和外周血细胞Foxp3 mRNA水平和TGF-？1、IL-10、IL-2、CD25、CD4、CDS、CD27、干扰素- γ、IL-6、tnf - α、CD80、CD86、CD28、CTLA-4、TLR-4和TLR-8将使用预扩增辅助实时定量PCR测定，并研究它们与急性排斥反应严重程度和可逆性的关系。特异性目的2：验证Foxp3调控网络基因mRNA水平预测同种异体肾移植功能和慢性同种异体肾病发展的假设。将从参加CTOT研究的肾移植受者连续收集尿液和外周血标本，并测量Foxp3 mRNA水平和Foxp3调节网络基因mRNA水平（列在SA1下），并研究它们预测(a)移植功能和(b)慢性同种异体移植肾病发展的能力。我们的研究，通过研究临床重要结果的强大细胞机制，可能导致异体移植受体的个体化治疗，并告知治疗，包括考虑输注Treg细胞来管理异体移植受体。

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.