Tumorvaccination using dendritic cells: impact of dendritic cell subsets, maturation inducing stimuli and IL-2.
Project management at the University of Würzburg:
Dendritic cells (DC) are antigen presenting cells of the immune system which can be generated in vitro from peripheral blood monocytes in a standardised manner. These culture methods and the availability of tumor specific antigens paved the way to use peptide loaded DC as a cellular vaccine in clinical trials. Recently we were able to demonstrate the induction of peptide-specific CTL activity ("proof of principle") in melanoma patients. However, a therapeutical breakthrough in metastasized melanoma has not been achieved yet. DC can develop from a variety of lymphoid and myeloid progenitors and also from more differentiated cells like blood monocytes and plasmacytoid lymphocytes. Depending on their origin and culture conditions the resulting DC populations vary in their functional behaviour. While in humans TH1 responses are preferentially induced by CD4+ DC, CD8+ DC seem to fulfil this job in mice. In addition, DC can be tuned in their functional orientation and need "danger signals" to develop from a functional resting "immature" state displayed in peripheral tissues into an immunostimulatory mature DC that migrates into draining lymph nodes and stimulates naive T cells. Recent observations suggest that priming of naive T cells requires antigen specific serial interaction of a given T cell with many DC. This finding is of wide range importance for vaccination concepts, since the induction of specific immunity and its functional characteristics (TH1/TH2-balance) will thus depend on a DC "Milieu" rather than on the immunostimulatory capacity of a single DC. Taken together the pinching question arises, whether an optimal immune response requires that in lymphoid tissues the relevant antigen is presented in sufficient quantity by the best suited DC-subset matured with the most potent stimuli. Furthermore it remains to be clarified, how often vaccinations have to be performed and whether there is a therapeutical benefit of boosting the immune response with interleukin 2. This project aims at finding answers to those questions.
Projekt period: from 05.2002 to 04.2004