Die Wirkung von zerebral exprimiertem Interleukin-12 auf die Gliomentwicklung ineinem transgenes Mausmodell

This thesis examines the effect of interleukin-12 (IL-12) on a murine stereotactically implanted brain tumor. It has already been demonstrated in a number of tumor models that IL-12 inhibits tumor growth. This could also be demonstrated to some extent in humans. A tumor model was established in which 3x104 GL261 type glioma cells were implanted stereotactically into the cerebellum of laboratory mice. The effect of transgenically expressed interleukin-12 in the cerebellum was examined in laboratory mice which over-expressed IL-12 and, for reasons of comparison, in wild-type animals. Literature describes numerous models which deliver interleukin-12 to the organism externally via viruses, gene gun, naked DNA injection or subcutaneous injection. In our model we examined endogenous over-expression of IL-12 in the cerebellum. Our results showed that GF-IL 12 tg laboratory animals had markedly fewer symptoms than wild-type animals. On average, tumor volumes in the GF-IL 12 tg laboratory animals were 64% smaller than in the wild-type animals. This was statistically significant. (p ≤ 0.0013, Mann Whitney U-Test). In immunohistochemical tests, we demonstrated that CD8+ T-cells, in particular, had infiltrated tumor tissue in GF-IL 12 tg laboratory animals. Later depletion experiments underlined the key role of the CD8+ T-cells. We were also able to demonstrate the suppressor function of CD4+ T-cells on CD8+ cells. We examined the role of NKcells, which have a subordinate role in this model, using CRAG animals. Finally, using IFN-gamma KO animals, we were able to show that IFN-gamma is not necessary for recruitment of CD8+ T-cells and tumor rejection. Even today, surgical resection followed by chemotherapy and radiotherapy remains the standard therapy for malignant gliomas. Immunotherapy with IL-12 could improve courses here. This thesis shows the fundamental ways in which endogenous IL-12 production mediates tumor rejection. IL-12 therapies of malignant gliomas in humans are still at the trial stage, however.