Thymectomy abrogates resistance to ethylnitrosourea-induced carcinogenesis in the peripheral nervous system of BDIV rats

3908 The knowledge about genes and effector mechanisms mediating susceptibility and resistance towards the development of malignant tumors is limited. The induction of malignant tumors of the peripheral nervous system (PNS; schwannomas) by the alkylating carcinogen N-ethyl-N-Nitrosourea (EtNU) in rats of the inbred BD strains is a suitable model to examine the mechanisms leading to differential tumor susceptibility. While > 85% of rats of the BDIX strain develop malignant schwannomas predominantly of the trigeminal nerves BDIV rats are almost completely resistant.A point mutation in the transmembrane region of the neu/erbB-2 gene is an early event in EtNU-incuced PNS carcinogenesis and has proved to be a marker of Schwann precursor cells at high risk of subsequent malignant transformation. Previous quantitative mutation analyses in trigeminal nerves of EtNU treated BDIV and BDIX rats revealed that tumor resistance mechanisms in the BDIV rat include recognition and elimination of neu -mutant premalignant cells.To uncover the underlying cellular and molecular processes, the involvement of a cellular immune response was investigated using immunohistochemistry on sections of trigeminal nerves from different time points after carcinogen exposure. A significant increase of CD8 + cytotoxic T cells, CD4 + T helper cells and ED1 + macrophages was detected in both rat strains after exposure to EtNU compared to the untreated controls. However there was no difference in cell numbers between resistant BDIV and sensitive BDIX rats making it uncertain whether T cells play a functional role in the elimination process. Therefore T cell maturation was prevented in BDIV rats by thymectomy after EtNU treatment on postnatal day one. In an ongoing study one group of rats was thymectomized for long time observation of tumor development (maximum 24 months). To monitor the efficiency of thymectomy peripheral blood T cells were quantified by FACS analysis at different time points. A second group of animals was operated for potential detection of residual T cells in trigeminal nerves by immunohistochemistry.So far a significant proportion (20%) of thymectomized BDIV rats developed malignant schwannomas, predominantly of the trigeminal nerves after a median latency time of 217 days with the great majority of thymectomized animals being still alive. These data demonstrate the important role of T cells in the prevention of EtNU-induced tumor development in the PNS of BDIV rats and suggest that the T cells in BDIX rats might display insufficient function regarding the elimination of premalignant Schwann cells, so that functional differences of the T cell response might translate into tumor susceptibility and resistance of BDIX and BDIV rats. Alternatively individual tumor risk in BD rats could be related to the different capability to escape or inhibit T cells by mechanisms yet unknown.