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.
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|Anglicheau, Dany; Muthukumar, Thangamani; Suthanthiran, Manikkam (2010) MicroRNAs: small RNAs with big effects. Transplantation 90:105-12|
|Anglicheau, Dany; Sharma, Vijay K; Ding, Ruchuang et al. (2009) MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci U S A 106:5330-5|
|Anglicheau, Dany; Suthanthiran, Manikkam (2008) Noninvasive prediction of organ graft rejection and outcome using gene expression patterns. Transplantation 86:192-9|