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Faßbender, Julia (2015): Etablierung eines Immunhyperthyreosemodells an der Maus zur Behandlung von Morbus Basedow. Dissertation, LMU München: Tierärztliche Fakultät



The objective of this thesis was the development of a mouse model for human Graves’ disease which ensures constant symptoms over a period of several months. Background is the assumption that a possible therapeutic development is only feasible and sensible on reliable animal models. The in-vivo parameters heart rate and weight development should therefore be reviewed as to their significance on the progression of the disease. In this study, BALB/c mice were immunized nine times with a TSHR-expressing adenovirus over a period of nine months. Alternatively, mice were administered adenovirus which expressed GFP ("mock-immunization). Both adenoviruses were given at concentrations of 1 * 1010 and 1 * 1011. Additionally, blood and ECG tests took place on a naïve, unimmunized mouse group. Before each immunization, body weight and heart rate of the animals were documented. The blood sera of the mice were examined for TSHR-stimulating antibodies with two different ELISA as well as determination of cAMP in test cells. A measurement of thyroxin took place at four time points (trial weeks 0, 8, 27 and 35). At the end of the test, the thyroid glands and hearts were investigated with regard to their dimensions and histological sections were examined. Increasing antibody titers were evidenced only in the Ad-TSHR-immunized animals. The mouse “third generation” assay which was adopted from a respective human assay delivered reliable results. Also these animals showed an increase of T4 levels compared to the control groups. The parameter heart rate proved to be a good indicator of the course of the disease. The heart rates of the Ad-TSHR-immunized mice increased considerably as well as the antibody titers. Observing the weight trend was unsuitable for the disease course assessment. However, the histological examination showed considerable differences between both groups. In Ad-TSHR-immunized animals, typical changes were verified, such as hyperplasia and a folding of the follicular epithelium and a marked vacuolization of the follicles. With the titer 1 * 1010 more stable results could be achieved than with 1 * 1011, especially on the parameters increase in serum T4 and the enlargement of the thyroid gland. The histological result of these animals was inconspicuous. In summary, a long-term immunization over a nine month period with TSHR-expressing adenovirus used at concentrations of 1 * 1010 and 1 * 1011 ensures maintenance of Graves’ disease symptoms for a period of at least 30 weeks and can provide an important contribution in preclinical research. Existing adenovirus protocols could therefore be validated for a considerably longer timeframe than was previously known. The measurement of the heart frequency represents a useful addition to existing mouse models.