Biomolecular Markers for Safe Minimization of Immunosuppression

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The overall gear is to build on the progress we have made and to leverage our recent ground-breaking advances in gene expression profiling technologies. SPECIFIC AIM 1: To perform broad, unbiased, deep sequencing of urine from kidney graft recipients undergoing surveillance and/or for-cause biopsies and discover new mRNA and miRNA signatures diagnostic and prognostic of acute rejection (AR), subclinical AR (SAR) and chronic allograft nephropathy (CAN) (SA. IA) and develop novel parameters for characterizing the in-vivo immune status of kidney graft recipients and the adequacy of their immunosuppressive therapy (SA. IB). SPECIFIC AIM 2: To test whether a previously discovered 3-gene signature of ISS-normalized C D 3 E and IP-10 mRNA, measured in sequential urine specimens, predicts the subsequent development of AR and SAR (SA. 2A); to test whether a previously discovered 4-gene signature of vimentin, NKCC2, E-cadherin and 18S rRNA, measured in sequential urine specimens, predicts the subsequent development of CAN (SA. 2B); and to test whether a miRNA panel comprised of miR-21, -21*, -30a-3p, -100; -142-3p/5p, -192, -194, - 200b, -222; and -223, measured in sequential urine specimens, predicts the subsequent development of AR, SAR and CAN (SA. 2C). SPECIFIC AIM 3: To test whether the previously discovered signatures and the miRNA panel, measured in sequential urine specimens, are associated with the type of induction therapy (T cell depleting antibody induction vs. anti-IL-2 receptor mABs induction) and with maintenance . immunosuppressive therapy (tacrolimus vs. no tacrolimus). Messenger RNAs and microRNAs, discovered by sequencing to be associated with AR, SAR and CAN (SA. 1) and measured in sequential samples (SA. 2), will be incorporated in statistical analyses to determine: (1) whether the previously identified signatures can be further optimized to improve their diagnostic and prognostic utility; and (2) whether the previously identified signatures can be further refined to improve their ability to track the influence of induction therapy and maintenance therapy on the immune status of kidney graft recipients. RELEVANCE (See instructions): An excess of immunosuppressive drugs is associated with infections, malignancy and cardiovascular and metabolic aberrations in organ graft recipients whereas inadequate immunosuppression is associated with allograft rejection. Thus, immunosuppression optimization is a major goal in organ transplantation. We propose to develop gene-based prognostic and diagnostic tests for characterizing the in-vivo immune status of kidney graft recipients and for monitoring the adenuacv of their immunosuppressive therapy.