Claudia Curci1,2, Fabio Sallustio1,3, Grazia Serino4, Giuseppe De Palma1,2, Mirko Trpevski1, Marco Fiorentino3, Michele Rossini3, Marco Quaglia5, Marialuisa Valente6, Lucrezia Furian7, Alessia Toscano8, Gianna Mazzucco9, Antonella Barreca9, Stefania Bussolino9, Loreto Gesualdo3, Piero Stratta5, Paolo Rigotti7, Franco Citterio8, Luigi Biancone9, Francesco P Schena1,2. 1. C.A.R.S.O. Consortium, University of Bari, Bari, Italy. 2. Schena Foundation, Research Center of Renal Diseases, Bari, Italy. 3. Renal, Dialysis and Transplant Unit, Department of Emergency and Organ Transplant, University of Bari, Bari, Italy. 4. Laboratory of Experimental Immunopathology, IRCCS 'de Bellis', Castellana Grotte, Bari, Italy. 5. Nephrology and Kidney Transplant Unit, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy. 6. Department of Cardiac, Thoracic and Vascular Sciences, Medical School, University of Padua, Padua, Italy. 7. Kidney Pancreas Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy. 8. Renal Transplantation Unit, Department of Surgery, Catholic University, Rome, Italy. 9. Nephrology, Dialysis and Kidney Transplantation Unit, Department of Medical Sciences, University of Torino, Torino, Italy.
Abstract
BACKGROUND: Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS: RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies. RESULTS: We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens. CONCLUSIONS: These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR.
BACKGROUND: Chronic T cell-mediated rejection (TCMR) in kidney graft is characterized by reduction of the vessel lumen with marked intimal thickening, fibrous hyperplasia of the small renal arteries and leukocyte infiltrates. The aim of this study was to find specific gene expression profiles in chronic TCMR kidney biopsies. METHODS: RNA extracted from archival formalin-fixed, paraffin-embedded renal biopsies was used for gene expression profiling. Our study included 14 patients with chronic TCMR and 10 with acute TCMR. Fifty-two cadaveric donors were used as controls. The results were validated in an independent set of kidney biopsies. RESULTS: We identified 616 and 243 differentially expressed genes with a fold change ≥1.5 and a false discovery rate <0.05 in chronic and acute TCMR, respectively. Pathway analysis revealed upregulation of OX40 signalling. This pathway is involved in the generation of CD8+ effector memory T cells and the upregulation of killer cell lectin-like receptor G1 (KLRG-1), B lymphocyte-induced maturation protein 1 (BLIMP-1) and CD25, which characterize CD8+ effector memory T cells. However, the enhanced OX40 signalling pathway was specific to chronic TCMR; a significant increase of KLRG-1+/CD8+ and BLIMP-1+/CD8+ was only detected in these specimens. CONCLUSIONS: These results suggest the involvement of memory-committed CD8+ effector T cells in chronic TCMR. The generation of effector memory T cells is mediated by the OX40 gene pathway, and could be considered a future target for the specific treatment of chronic TCMR.
Authors: Xingqiang Lai; Xin Zheng; James M Mathew; Lorenzo Gallon; Joseph R Leventhal; Zheng Jenny Zhang Journal: Front Immunol Date: 2021-05-20 Impact factor: 7.561
Authors: Toshihito Hirai; Aaron T Mayer; Tomomi W Nobashi; Po-Yu Lin; Zunyu Xiao; Tomokatsu Udagawa; Kinya Seo; Federico Simonetta; Jeanette Baker; Alan G Cheng; Robert S Negrin; Sanjiv S Gambhir Journal: JCI Insight Date: 2021-07-08