Deciphering the role of Tribbles Homolog 1, a novel biomarker in transplantation – TRIB1

Diagnosing the different causes of late allograft injury is a major challenge in transplantation but is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. One of the main axes of our research group is the discovery of novel minimally-invasive biomarkers of chronic rejection in renal transplant patients. The project described herein is specifically dedicated to the downstream analysis of one such molecule. By comparing gene sets from published microarray studies of late kidney graft injury, we identified Tribbles Homolog 1 (TRIB1), a relatively unknown human homolog of drosophila tribbles, as being present in several gene lists and thus a potentially informative biomarker. TRIB1 mRNA expression profiling in 54 graft biopsies and 46 blood samples from independent cohorts of renal transplant patients with different histological diagnoses recruited at two European centers, established this molecule as a potential tissue and blood surrogate biomarker of Chronic Humoral Rejection (CHR), an active immune-mediated form of chronic graft failure associated with a poor prognosis. These results were reproduced in a rodent model of chronic cardiac vasculopathy, indicating the relevance of TRIB1 to cardiac as well as renal transplantation. In healthy individuals TRIB1 is expressed primarily by monocytes, and dendritic cells, indicating a role for these cells in CHR. The aims of this project are 1) to determine the exact cell type at the origin of the increase in TRIB1 in the blood and in the graft, 2) to discover the function of TRIB1 in monocytes and dendritic cells, and 3) to determine the phenotype of mice in whom TRIB1 has been genetically invalidated. ...