Effect of double knockout of anaphylatoxin receptors C3aR and C5aR1 on regulatory T cells in rapid progressive glomerulonephrtis
We aim to address the effect of the anaphylatoxin receptors C3aR and C5aR1 on regulatory T cells in rapid progressive glomerulonephritis and to evaluate a direct manipulation of these anaphylatoxin receptors as a possible therapeutic option in rapid progressive glomerulonephritis. We plan to analyse the localization and expression of C3aR and C5aR1 in kidney biopsies from patients with confirmed ANCA-associated glomerulonephritis by single cell analysis and immunohistochemistry and to compare the results with healthy controls. Of particular interest is the expression pattern of C3aR and C5aR1 in the different immune cells. Conspicuous expression patterns of the anaphylatoxin receptors will then be further investigated in the animal model. In the corresponding mouse model the reproducibility of the human data will be checked. In addition, the immune response in C3aR x C5aR1 double knockout mice with nephrotoxic glomerulonephritis will be evaluated and compared to a wild type cohort. Here, any influence of the double knockout on regulatory T cells and TH17 cells will be analysed. Finally, to test a possible therapeutic relevance of the anaphylatoxin receptors for rapid progressive glomerulonephritis, the renal damage pattern in glomerulonephritis will be compared between the C3aR x C5aR1 double knockout and wild type group. For this purpose, various parameters of end organ damage, such as histological renal damage and GFR will be collected. Since preliminary data suggest that the two receptors may regulate regulatory T cells in a sex-differentiated manner, the experiments will be performed in male and female mice.