Anja Lemke1, Mercedes Noriega2, Anja M Röske3, Markus J Kemper4, Björn Nashan5, Christine S Falk6, Martina Koch7. 1. Department of Hepatobilary and Transplant Surgery and Pediatric Nephrology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; University Childrens Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: lemke_anja@gmx.de. 2. Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: m.noriega@uke.de. 3. Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: anjaroeske@live.com. 4. University Childrens Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: kemper@uke.de. 5. Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: nashan@uke.de. 6. Institute of Transplant Immunology, IFB-Tx, Hannover Medical School, Hannover, Germany; Deutsches Zentrum für Infektionsforschung DZIF, Heidelberg, Germany. Electronic address: Falk.Christine@mh-hannover.de. 7. Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: martina.koch@uke.de.
Abstract
BACKGROUND: Acute renal allograft rejection remains a major cause of allograft dysfunction; especially for episodes with mixed humoral and cellular character which can be detrimental for graft survival. We established a rat RT model with exclusive and complete MHC-disparity to investigate pathomechanisms of acute rejection and evaluate serum multiplex assays as a diagnostic tool in this context. METHODS: LEW rats receive congeneic LEW.1W allografts (allo), no immunosuppression. Planned duration of the experiment was 4 weeks (n = 13 allo, n = 3 iso). To study kinetics of rejection, additional animals were sacrificed at day 7 (n = 6 allo and n = 3 iso) and day 21 (n = 3 allo). Serum cytokines and chemokine were longitudinally analyzed with multiplex assays in n = 5 allo and n = 5 controls. Allografts were assessed by histopathology, immunohisto-chemistry and PCR. RESULTS: Animals develop allograft dysfunction acute humoral rejection with additional cellular components. Donor-specific MHC-antibodies are already detectable at day seven (d7) after RT. Leukocytic graft infiltrates are dominated by macrophages and additionally consist of T-cells, B-cells and NK-cells. Increased intragraft expression of interleukin-2, interferon gamma, tumor necrosis factor alpha as well as B-cell activating factor and its receptor are observed. Of the 24 serum cytokines/chemokines, only CCL2 is significantly different (higher)in allo vs. controls at d7 (p = 0.02). CONCLUSIONS: Correlation of serum chemokines/cytokines with features of humoral and cellular rejection, as reproduced in our LEW.1W to LEW rat renal transplant model, is limited. Macrophages, B-cells and their signaling pathways deserve more attention in genesis and possibly also treatment of acute rejection.
BACKGROUND: Acute renal allograft rejection remains a major cause of allograft dysfunction; especially for episodes with mixed humoral and cellular character which can be detrimental for graft survival. We established a rat RT model with exclusive and complete MHC-disparity to investigate pathomechanisms of acute rejection and evaluate serum multiplex assays as a diagnostic tool in this context. METHODS: LEW rats receive congeneic LEW.1W allografts (allo), no immunosuppression. Planned duration of the experiment was 4 weeks (n = 13 allo, n = 3 iso). To study kinetics of rejection, additional animals were sacrificed at day 7 (n = 6 allo and n = 3 iso) and day 21 (n = 3 allo). Serum cytokines and chemokine were longitudinally analyzed with multiplex assays in n = 5 allo and n = 5 controls. Allografts were assessed by histopathology, immunohisto-chemistry and PCR. RESULTS: Animals develop allograft dysfunction acute humoral rejection with additional cellular components. Donor-specific MHC-antibodies are already detectable at day seven (d7) after RT. Leukocytic graft infiltrates are dominated by macrophages and additionally consist of T-cells, B-cells and NK-cells. Increased intragraft expression of interleukin-2, interferon gamma, tumornecrosis factor alpha as well as B-cell activating factor and its receptor are observed. Of the 24 serum cytokines/chemokines, only CCL2 is significantly different (higher)in allo vs. controls at d7 (p = 0.02). CONCLUSIONS: Correlation of serum chemokines/cytokines with features of humoral and cellular rejection, as reproduced in our LEW.1W to LEW rat renal transplant model, is limited. Macrophages, B-cells and their signaling pathways deserve more attention in genesis and possibly also treatment of acute rejection.
Authors: Laura Kummer; Marcin Zaradzki; Vijith Vijayan; Rawa Arif; Markus A Weigand; Stephan Immenschuh; Andreas H Wagner; Jan Larmann Journal: Front Physiol Date: 2020-05-08 Impact factor: 4.566