Ischemia reperfusion injury (IRI) contributes to acute allograft injury and to delayed graft function (DGF) which is a trigger for acute rejection after kidney transplantation (ktx). After initial activation of myeloid cells in the first 48 hours after IRI, T-cells invading the renal tissue are relevant producers of the pro-inflammatory mediator IL-17A. In this project, we evaluated the role of T-cell subsets (αβversus γδ T-cells) and IL-17A on inflammation in IRI and ktx models in mice.

IRI was induced by unilateral clamping of the renal pedicle for 45min. In an allogenic kidney transplant (ktx) model prolonged cold ischemia time of 60min was used to induce DGF and consecutive ktx rejection. In both models follow up was 7 days and infiltrating leukocytes were quantified by flow cytometry. T-cell receptor (TCR-γδ), IL-17A deficient and wildtype (WT) control mice were compared in the IRI model and served as recipients in the ktx model with fully mismatched WT allografts from C57BL/6 donors. Histology, immunohistochemistry and qPCR were done to characterize inflammation.

IRI and ktx resulted in substantial T-cell infiltration but the distribution of T-cell subsets were different. In IRI αβ T-cell infiltrates were 8 fold higher compared to γδ T-cells whereas in the combination of DGF with ktx αβ T-cell infiltrates were about 80 fold higher compared to γδγ T-cell infiltrates. The γδ T-cells contributed substantially to elevated IL-17A production. Surprisingly, TCR-γδ and IL-17A deficient mice were not protected from IRI and showed progressive renal fibrosis similar to WT mice. In both mouse strains (TCR-γδ and IL-17A deficient mice) IL-17A production of γδ T-cells was totally abrogated in ex vivo T-cell stimulation with PMA/ionomycin.

Conclusion: Surprisingly, neither γδ T-cell nor IL-17A deficiency attenuated IRI induced renal inflammation or fibrosis.

CITATION INFORMATION: Thorenz A, Rong S, Völker N, Chen R, Bräsen J, Haller H, Klemann C, Gueler F. Contribution of γδ T-Cell Subsets and IL-17A Release to Ischemia Reperfusion Injury (IRI) and Kidney Allograft Rejection in Mice. Am J Transplant. 2017;17 (suppl 3).

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