The goals of this revised renewal application are based on the new information we acquired in the previous funding period and the overall accumulation of knowledge in the DC field in general. Seven years ago, the state-of-the-art knowledge divided DC into two subsets, lymphoid and myeloid. Within each subset, they could exert either immunogenic or tolerogenic effects, depending on the state of maturation and the ability to provide to naive T cells antigenic and co-stimulatory factors (signal 1 and signal 2). Much more is known now about DC subsets and their ability to provide T cells with specific signals that differentially regulate the development of Th1 and Th2 responses control the state of immunity as well as tolerance. Our goals are 1) to understand what specific DC subsets do in vitro and in vivo to affect customized responses to distinct antigen, in particular tumor antigens; 2) to understand how their in vivo function can be modulated in animal models; 3) to test DC as therapeutic agents in the clinic. In three projects and two cores we are testing several hypotheses: hypothesis I is that DC regulate immune responses and determine the difference between a beneficial and a detrimental outcome; hypothesis II is that specific subsets of DC may be a useful vaccination tool to induce the immune responses with a desired character; hypothesis III is that the ability of DC subsets to control immunity and types of immune responses, depends on the expression of specific co-stimulatory molecules as well as the production of specific cytokines; hypothesis IV is that the form of antigen that is encountered by the DC is an important factor in the final outcome.
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