Abstract
Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation.
Highlights
Despite marked improvement in short-term graft outcome through reduced incidence of acute T-cell-mediated rejection (TCMR) with the current immunosuppressive armamentarium, long-term kidney allograft survival remains suboptimal [1, 2]
The cell–cell contact of immune cells with GENC was required for cytokine production, illustrated by the higher cytokine levels in cocultures of immune cells with GENC compared to immune cells alone (Supplementary Figure S9). In this representative cohort of consecutive samples from kidney transplant recipients at time of allograft dysfunction, we demonstrate that pro-inflammatory cytokines in the peripheral blood associate with presence of human leukocyte antigens (HLA)-donor-specific antibodies (DSA) and impaired kidney transplant survival
These pro-inflammatory blood signals associate with HLA-DSA, rather than with rejection phenotypes as identified in kidney transplant biopsies. This illustrates that HLA-DSA can lead to immune activation that is not always reflected in histology of the concomitant kidney transplant biopsies
Summary
Despite marked improvement in short-term graft outcome through reduced incidence of acute T-cell-mediated rejection (TCMR) with the current immunosuppressive armamentarium, long-term kidney allograft survival remains suboptimal [1, 2]. An important cause for this long-term graft failure is acute rejection, especially antibody-mediated rejection (ABMR) [3, 4]. Part of the explanation for the impaired graft survival associated with ABMR [7–10] is the lack of proven effective treatments to prevent or treat ABMR [4, 11, 12]. In the search for biomarkers and therapeutic targets for acute rejection, several research groups have suggested to study cytokines, as they play a crucial role in the pathophysiology of rejection [13–31]. Details on the specificity of some cytokines for allo-immune processes, different rejection subtypes and associated histological lesions is lacking
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