Aus Dem Lehrstuhl Für Immunologie Professor Dr. Daniela N. Männel Der Fakultät Für Medizin Der Universität Regensburg the Role of Tnfr2 in Experimentally Induced Glomerulonephritis

TNF is an important cytokine and acts as mediator of inflammatory tissue damage which is caused by immunologically mediated processes. TNF provides its effects via two signalling pathways using its two receptors, TNFR1 and TNFR2. In 2005 Vielhauer et al. revealed that TNFR2 plays an important role in the development of glomerulonephritis, which is one of the most important causes for renal failure and leads to proteinuria and renal dysfunction. Vielhauer found that TNFR2-/mice were protected from the development of glomerulonephritis. Based on this hypothesis, we intended to further investigate and, therefore, tried to reproduce it in our experimental setup of glomerulonephritis induction. As parameters for the development of glomerulonephritis we observed proteinuria and typical histological changes in the renal structure. We also tested whether we could find a correlation between the development of glomerulonephritis and the concentration of TNFR2 in urine. We found out that amounts of soluble mTNFR2 in urine showed no correlation to the severity of disease. However, we were not able to reproduce Vielhauer’s findings, since TNFR2-/mice in our setup were not protected against glomerulonephritis. We assumed that his findings could be explained by the presence of a so-called TNF-tolerance that has developed in the organism of TNFR2-/mice because of former exposure to higher levels of TNF. Furthermore, we intended to study the development of experimental glomerulonephritis in mice that were transgenic for human TNFR2 (hTNFR2), which is able to interact with mouse TNF in a functional way. Working with these transgenic mice, we were able to establish an easy and reproducible way to identify mice that were transgenic for the hTNFR2 by detecting soluble hTNFR2 in urine of these mice. Contrary to our expectations, mice transgenic for hTNFR2 showed no signs of increased pathology and no enhanced inflammatory response to the induction of glomerulonephritis. One possible explanation may be provided by the fact that the mice we used in our experimental setup were exposed to constitutive overexpression of hTNFR2 instead of disease-correlating levels of mouse TNFR2 which may have an important impact on the development of glomerulonephritis. According to these findings, we assumed that inducing glomerulonephritis in mice according to our experimental protocol has no striking impact on the concentration of signalling TNFR2. Contrary to Vielhauer’s assumptions, antagonizing TNFR2 might not provide such special improvement in treatment of glomerulonephritis as TNF blockade does in the current clinical treatment of other chronic inflammatory diseases such as inflammatory bowel diseases or rheumatoid arthritis. Table of