Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Mooslechner, A.
The role of CD8+ T cells in Nephrotoxic Serum Nephritis:
Low-dose IL-15 as potential immunotherapy to treat Glomerulonephritis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2023. pp. 101
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- Autor*innen der Med Uni Graz:
- Mooslechner Agnes Anna
- Betreuer*innen:
- Eller Kathrin
- Sourij Harald
- Strobl Herbert
- Altmetrics:
- Abstract:
- Introduction: Rapid-progressive glomerulonephritis (GN) often progresses to end-stage renal disease, which poses a global health burden by creating the need for renal replacement therapy. Current treatments often involve non-selective immunosuppressants, which increase the risk of infections and malignancies. A better understanding of the underlying pathomechanism is needed to design new directed interventional therapies. The involvement and role of CD8+ T cells in the onset and progression of GN are still not clear, partly due to conflicting literature published. In this study, we addressed this question in a mouse model of nephrotoxic serum nephritis (NTS), mimicking a form of non-autoimmune GN. IL-15 is a pleiotropic cytokine, which has previously been associated with kidney health and tubular epithelial cell (TEC) survival, but also with a memory shift in the CD8+ T cell population. We investigated the potential of low-dose IL-15 as an intervention in our NTS model, focusing on the effects on the CD8+ T cell population. Methods: To investigate the involvement of CD8+ T cells, we subjected CD8α-/- mice to NTS and analyzed disease outcomes after 21 days of disease. Additionally, we used a CD8α antibody-mediated depletion approach in C57Bl/6J wildtype mice subjected to NTS. We identified urinary albumin to creatinine ratio (ACR), glomerulosclerosis, myeloid cell infiltration of the kidney, and blood urea nitrogen levels as relevant disease outcomes. In our second set of experiments, we administered low-dose IL-15 on day 1 of NTS as an intervention in C57Bl/6J mice. After 7 days of disease, we analyzed ACR, glomerulosclerosis, and myeloid cell infiltration of the kidney and focused on TEC injury. We investigated IL-15-mediated effects on CD8+ T cells in detail. We used genetic knockout mice of the IL-15Rα and CD8α-/- mice to understand the point of activity of IL-15. Finally, we investigated the long-term effects of our single low-dose IL-15 therapy schedule in 21 days of NTS. Results: Absence of CD8α in genetic knockout mice and wild-type mice that received depletion antibodies resulted in aggravated disease. Glomerulosclerosis and macrophage infiltration was increased in these mice compared to respective control groups. Interestingly, CD8α-/- mice presented with higher BUN levels. Low-dose IL-15 therapy improved ACR, glomerulosclerosis, and TEC survival on day 7 of NTS. We found no differences in iNKT and CD4+ Treg cell numbers. However, CD8+ T cells showed a decrease in Prf1, Gzmb, and Ifnγ relative gene expression, while Ikzf2 expression was increased. In addition, CD8+ T cell memory subsets, including Ly49+CD8+ memory T cells, were increased in the treatment group. IL-15Rα-/- mice and CD8α-/- mice showed no benefit in disease outcomes by IL-15 therapy. After 21 days of NTS, the benefits of single low-dose IL-15 administration were not as pronounced as on day 7. Conclusion: We found no evidence that overall CD8 depletion or genetic knockout is beneficial in NTS. On the contrary, CD8α-/- mice displayed an aggravated disease phenotype with increased macrophage influx and an association with a striking decline in kidney function, suggesting a partly protective role of CD8+ T cells. We improved the NTS phenotype in mice with a low-dose IL-15 interventional therapy, partly by protecting TECs from cell death in a CD8-dependent manner. Due to administered IL-15, CD8+ T cells presented with a less cytotoxic phenotype and the upregulation of the regulatory associated marker Helios. In addition, we noted a clear shift of the population to an increase in memory cells, including supposedly regulatory Ly49+CD8+ memory T cells, which are the murine counterpart to human KIR+CD8+ T cells. To summarize, although the involvement of CD8+ T cells in NTS is complex, we propose IL-15 as a potential cytokine-based immunotherapeutic approach to treat GN, with a need for further translational studies.