IL-15 mediated activation of CD8+ T cells as treatment target in human septic Acute Kidney Injury

• Applicant: Professor Dr. Philipp Enghard
• Subject Area: Nephrology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 552696103

Acute kidney injury (AKI) is one of the most common causes of kidney function impairment. Data from mouse models show a central role of inflammatory cells migrating into the kidney tissues in AKI. In preliminary work, using urine and kidney biopsy samples from patients with AKI, we have shown that CD8+ T cells (so-called killer T cells) migrate into the kidney tissue and can also be observed in the urine. These cells have an activated state and correlate with kidney damage. IL-15, a messenger produced in the kidneys in AKI, can activate these cells, resulting in damage to adjacent kidney cells. Interestingly, the antibiotic cefazolin inhibits IL-15, and we have preliminary evidence that this may lead to a beneficial modulation of the immune response in AKI. In the proposed project, we will investigate the role of the CD8+ T cell in human AKI. To this end, we will use the analysis of cells in urine as a "window into the kidneys" to investigate the precise interplay between CD8+ T cells and kidney injury during the course of AKI. In kidney biopsies from deceased patients, the exact spatial relationship between CD8+ T cells, damaged kidney cells and activating factors such as IL-15 will be described. In cell culture experiments, the interaction between CD8+ T cells and renal cells will be functionally investigated, including blockade of IL-15. Finally, in a clinical observational study, the impact of cefazolin on the local immune reaction in AKI will be analyzed using urinary cells as a proxy for intrarenal inflammation. In summary, we hope that the proposed project will provide crucial insights into the pathogenesis of human AKI and the first evaluation of a possible targeted therapeutic intervention.

• DFG Programme: Research Grants