The immune system evolved to respond to pathogens, whilst limiting self-tissue damage. Unique antigens presenting cells, called dendritic cells (DC) initiate immune responses upon encounter with foreign microorganisms or inflammatory stimuli trigger innate immune responses that represent the first line of defence against invading pathogens. Subsequently, activated DC prime antigen-specific immune responses that clear the infections and give rise to immunological memory. This proposal is to develop in sito DC targeting for use as vaccines in infectious diseases and cancer. We will define improved reagents and protocols for antigen delivery and targeting, to improve antigen processing and presentation by DC for use in vaccine technology. A comparison will be made on peptides, proteins, RNA, DNA and antigen modifications that allow presentation via MHC molecules. Recombinant bacteria and viral vectors are most suitable for the transduction of etherologous model antigens into DC.
Different approaches will be undertaken to develop microbial vectors delivering antigens to DC with the highest efficiency for presentation via MHC class I and II molecules. Preliminary results show that DC loaded with recombinant bacteria and injected in vivo are capable of protecting mice for tumour challenge. Recombinant viruses, some encoding poliepitopes, will also be used as vectors to target DC. CTL primed by virus infected DC have cytolytic activity and can protect mice from tumour challenge. Viral vectors will also be generated to exploit the promoter regions of DC specific C-type lectins such as DC-SIGN to target and deliver model and tumour antigens to DC, and these will be cloned in mouse and humans and used to drive the expression of model and tumour antigens. Such approaches will be tested in mouse and human DC systems in vitro for their capacity to activate CD4+ and\or CD8+ Tcells in comparison with known DC maturation and activation stimuli.
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