FoxP3 Regulatory Network mRNA Profiles and Human Renal Transplant Outcomes

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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.