We propose to undertake a comprehensive mechanistic study to establish informative biomarkers in pediatric renal transplantation, using patient clinical data and tissue (biopsy and blood) from SNS01- a randomized clinical trial of steroid-free versus steroid-based immunosuppression. This proposal outlines a strategy for integrating clinical and pathology cores from SNS01 with genomic (cDNA arrays and real-time PCR) and immunopathology (core biopsies and tissue microarrays) cores, the latter two cores to be generated by this proposal.
The aims of this study are fourfold. (i) To develop diagnostic biomarkers by DNA microarray analysis, in tissue and blood for stable transplants, acute rejection (AR) and chronic allograft nephropathy (CAN). (ii) To detect differences in these graft states in steroid-free and steroid-based immunosuppression. (iii)To correlate the expression of selected highly differentiated genes in tissue and blood, using real-time PCR, to establish non-invasive blood markers for graft surveillance, AR diagnosis, classification, and stratification of AR therapy and outcome. (iv) To use immunohistochemistry analysis on core patient biopsies and tissue microarrays to correlate gene expression data with cellular infiltration phenotypes, density and activation in AR, CAN and normal post-transplant kidneys, in steroid-free and steroid-based immunosuppression. These studies are expected to facilitate the definition of immunological and cellular mechanisms underlying stable transplants and different forms of renal allograft dysfunction, different types of immunosuppression (with and without steroids), and generate clinical tools for non-invasive graft monitoring, as well as graft therapeutic and risk stratification. The genomic and tissue microarray databases will be made publicly available for the academic community to facilitate future large-scale collaborative studies. ? ? ? ?
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