As key mediators of the intercellular communication, cytokines play a crucial role in many processes following transplantation, including inflammation, tissue regeneration, and anti-microbial defense. Locally produced cytokines might reach the circulation, where they provide information about the processes in the transplanted organ. Assessing blood cytokine levels may help to understand the molecular mechanisms after transplantation and to identify novel therapeutic targets and predictive biomarkers. In our study, we individually quantified a wide range of cytokines, cytokine-like molecules and soluble cytokine receptors in serum obtained from kidney transplant (KTx) patients taken shortly before (day 0), at 1 week and 3 months after transplantation. Healthy blood donors served as control cohort. We identified 11 molecules including novel cytokines like IL-19 that were significantly increased at day 0 as compared to healthy individuals. Levels of most of these molecules clearly declined during the first week after KTx. Of interest, further evaluation revealed that patients developing acute cellular transplant rejection within the first post transplant year showed significantly different IL-22 blood levels already at 1 week after KTx as compared to KTx patients with a stable graft function. Furthermore, the extent of decrease of IL-22 binding protein (IL-22BP) differed between both patient subgroups. IL-22BP inhibits the activity of IL-22, a cytokine we demonstrated of to influence tissue but not immune cells. Stimulation experiments showed that IL-22 amplified the TNF-a/IL-17-induced IL-19 production by epithelial cells. In these cells, IL-19 in turn elevated the production of calprotectin known to promote inflammatory leukocyte/renal cell interactions. Systems biological analyses revealed further cytokine cascades that included both pro- and anti-angiogenic as well as antiviral mediators. Further studies are underway to identify the significance of identified cytokine cascades and the suitability of IL-22 as a biomarker for acute rejection in KTx patients.

CITATION INFORMATION: Sabat R, Witte E, Reinke P, Wolk K, Babel N. Cytokine Networks in Kidney Transplant Patients. Am J Transplant. 2016;16 (suppl 3).

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