Definition of TREG and TEFF/MEM transcriptional and proteomic profiles of liver transplant patients undergoing calcineurin inhibitors withdrawal

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Description: Calcineurin inhibitors (CNI) cyclosporine and tacrolimus (TAC) are standard immunosuppressive (IS) agents used to prevent allograft rejection following liver transplantation (LT). However, indefinite treatment with these agents causes chronic CNI toxicity, leading to chronic kidney disease, metabolic complications, infections, and malignancy. The use of non-nephrotoxic IS such as rapamycin inhibitor (mTOR-I) everolimus (EVL) could reduce these adverse effects. mTOR-I and CNIs have the opposite effect on regulatory T cells (TREG), which are important for controlling alloimmune responses. CNI reduces TREG generation, while mTOR-I promotes it. Molecular pathways that activate the interaction between TREG and TEFF/MEM in vivo during TAC withdrawal are unknown. We are using proteomics and transcriptional analyses of TREG and TEFF/MEM in LT recipients on mTORi who successfully underwent TAC withdrawal (EVL) versus rejection (INT-1) in comparison with those kept on TAC ± EVL (INT-2, and OBS-2). Integration of transcriptional and proteomics can provide mechanistic insights on TREG and TEFF/MEM molecular pathways in LT recipients and inform the identification of novel biomarkers of acute rejection.

 

Longitudinal study design for transcriptomics analysis and mass spectrometry-based proteomics of TREG and TEFF cells isolated from PBMCs from interventional and observational group patients.  After bottom-up and top-down proteomics is achieved, detected proteins will be assembled by network & pathway analysis and integrated with RNA-seq data for functional inference and hypothesis generation.

 

Project status: On going

Spinoff funding: U01 – 2022 to 2029