Anne Höfer1,2, Danny Jonigk3, Björn Hartleben3, Murielle Verboom4, Michael Hallensleben4, Stefan G Hübscher5,6, Michael P Manns1,7, Elmar Jaeckel1,2, Richard Taubert1,2. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany. 2. Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany. 3. Institute for Pathology, Hannover Medical School, Germany. 4. Institute for Transfusion Medicine, Hannover Medical School, Germany. 5. Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom. 6. Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom. 7. Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
Abstract
BACKGROUND: Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. METHODS: To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with "no histologic rejection" (NHR; n = 25), "clinical TCMR" (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays. RESULTS: SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. CONCLUSIONS: T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
BACKGROUND: Subclinical T cell-mediated rejection (subTCMR) is commonly found after liver transplantation and has a good short-term prognosis, even when it is left untreated. Donor-specific antibodies (DSA) are putatively associated with a worse prognosis for recipient and graft after liver transplantation. METHODS: To assess the immune regulation in subTCMR grafts, gene expression of 93 transcripts for graft injury, tolerance, and immune regulation was analyzed in 77 biopsies with "no histologic rejection" (NHR; n = 25), "clinical TCMR" (cTMCR; n = 16), and subTCMR (n = 36). In addition, all available subTCMR biopsies (n = 71) were tested for DSA with bead assays. RESULTS: SubTCMR showed heterogeneous and intermediate expression profiles of transcripts that were upregulated in cTCMR. Graft gene expression suggested a lower activation of effector lymphocytes and a higher activation of regulatory T cells in grafts with subTCMR compared to cTCMR. DSA positivity in subTCMR was associated with histological evidence of more severe graft inflammation and fibrosis. This more severe DSA+ associated graft injury in subTCMR was converged with an upregulation of cTCMR-associated transcripts. In nonsupervised analysis, DSA positive subTCMR mostly clustered together with cTCMR, while DSA negative subTCMR clustered together with NHR. CONCLUSIONS: T cell-mediated rejection seems to form a continuum of alloimmune activation. Although subTCMR exhibited less expression of TCMR-associated transcript, DSA positivity in subTCMR was associated with an upregulation of rejection-associated transcripts. The identification of DSA positive subclinical rejection might help to define patients with more inflammation in the graft and development of fibrosis.
Authors: Kerstin Herzer; Martina Sterneck; Martin-Walter Welker; Silvio Nadalin; Gabriele Kirchner; Felix Braun; Christina Malessa; Adam Herber; Johann Pratschke; Karl Heinz Weiss; Elmar Jaeckel; Frank Tacke Journal: J Clin Med Date: 2020-11-05 Impact factor: 4.241
Authors: Anne Höfer; Danny Jonigk; Björn Hartleben; Murielle Verboom; Michael Hallensleben; Michael P Manns; Elmar Jaeckel; Richard Taubert Journal: Sci Rep Date: 2020-08-28 Impact factor: 4.379
Authors: Safak Gül-Klein; Henriette Hegermann; Robert Röhle; Moritz Schmelzle; Frank Tacke; Wenzel Schöning; Robert Öllinger; Tomasz Dziodzio; Patrick Maier; Julius M Plewe; David Horst; Igor Maximilian Sauer; Johann Pratschke; Nils Lachmann; Dennis Eurich Journal: J Inflamm Res Date: 2021-06-23