Medizinische Universität Graz - Research portal
Selected Publication:
Kirsch, A.
Immune Cells in Renal Disease:
Regulatory T Cells in Nephrocalcinosis and TH9 Cells in
Nephrotoxic Serum Nephritis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2015. pp.98.
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- Authors Med Uni Graz:
- Kirsch Alexander
- Advisor:
- Eller Kathrin
- Rosenkranz Alexander
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- Abstract:
- The present doctoral thesis examined the role of different T cells subsets in two different experimental models of renal disease: Nephrocalcinosis is characterized by aberrant deposition of calcium in the kidneys and is seen in phosphate nephropathy, primary hyperparathyroidism, and distal renal tubular acidosis. To further evaluate the specific pathophysiologic role of T cells in ectopic calcification, we used DBA/2 mice that are prone to develop nephrocalcinosis and dystrophic cardiac calcinosis. Female DBA/2 mice were depleted of T cells or regulatory T cells (Tregs) using either an anti-CD3e or an anti- CD25 monoclonal antibody and compared with isotype-treated controls, respectively. After this immunomodulation, the DBA/2 mice were given a high-phosphate diet for 9 days and the degree of calcification was assessed by microcomputed tomography. Successful depletion was confirmed by flow cytometry of splenocytes. In DBA/2 mice, the high- phosphate diet induced a phenotype of nephrocalcinosis and dystrophic cardiac calcinosis. T-cell depletion significantly increased renal calcification in microcomputed tomography. Concordantly, Treg depletion significantly deteriorated acute phosphate nephropathy and was associated with a significantly increased mortality rate. Immunomodulation had no impact on the amount of cardiac calcification. Semiquantitative histopathologic evaluations with Alizarin Red staining independently confirmed the respective radiologic measurements. TH9 cells are a T helper cell subpopulation characterized by predominant secretion of interleukin 9 (IL-9). Functionally, TH9 cells have mainly been implicated in allergy. The cytokine IL-9 improves TH17 cell activation, regulatory T cell function and promotes mast cell proliferation. To date the role of TH9 cells in nephritis is unknown. In the present study, we therefore evaluated the role of TH9 cells in nephrotoxic serum nephritis (NTS). In healthy mice, TH9 cells localize predominantly to the lymph nodes. Upon NTS induction, a gradual increase in TH9 cells and the TH9-secreted chemokines CCL17 and CCL22 in the kidney is paralleled by their decrease in lymph nodes and spleen. To evaluate the role of TH9 cells, we subjected IL-9 knock-out (IL-9-KO) and wild- type (WT) mice to NTS. After 14 days, IL-9-KO mice displayed significantly decreased albuminuria, histological changes and renal inflammatory cell infiltration. Upon transfer of in vitro polarized TH9 cells into IL-9-KO mice, the WT phenotype was restored. Importantly, TH9 transfer restored leukocyte infiltration. In summary, the present doctoral thesis illustrates the pivotal contribution of T cells to renal pathogenesis across two experimental models of renal disease: Firstly, we suggest a pivotal role of T cells, particularly Tregs, in the progression of nephrocalcinosis and emphasize the fact that inflammation deteriorates the outcome in acute phosphate nephropathy. Secondly, we show that TH9 cells are essential for NTS, which may be explained by TH9 migration to the kidney and subsequent local secretion of CCL17 and CCL22 and CCR4+ cell recruitment.