Rat renal transplant model for mixed acute humoral and cellular rejection: Weak correlation of serum cytokines/chemokines with intragraft changes

Abstract

BackgroundAcute 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. MethodsLEW rats receive congeneic LEW.1W allografts (allo), no immunosuppression. Planned duration of the experiment was 4weeks (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. ResultsAnimals 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). ConclusionsCorrelation 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.