A major need in vaccine development is the identification of an efficient mechanism to target appropriate epitopes for effective presentation by antigen presenting cells (APCs) in vivo. Previous work by the applicants has focused on understanding the structure, function and cytokine regulation of Fc receptors for IgG (Fc/gamma/R) and on elucidating the antigens, mechanisms and immunization requirements important for immunity to T. gondii and group B streptococci (GBS). These divergent areas have become interrelated by our finding that Ag targeted specifically to Fc/gamma/R results in markedly more efficient T cell activation than Ag alone. One class of Fc/gamma/R, Fc/gamma/RI, in fact represents an attractive target molecule for antigen delivery because it is highly expressed only on mononuclear phagocytes and mediates Ag uptake via a pathway that leads to efficient T cell activation. However, the relative efficiency of targeting to other mononuclear phagocyte molecules is unknown, and the influence of cytokines on mononuclear-targeted Ag presentation is not well understood. In this application, we propose a systematic and comprehensive analysis of targeted Ag presentation specifically as it relates to Group B streptococcal infection and toxoplasmosis, with the goal of developing a candidate vaccine useful in preventing these diseases. More specifically, we would: 1) determine the relative efficacy for T cell stimulation in vitro of targeting Ag to human mononuclear phagocytes via different cell surface molecules. We will compare responses using non-targeted Ag and Ag targeted to Fc/gamma/R or to other mononuclear phagocyte receptors and determine whether dual targeting of Ag by two different mononuclear receptors results in greater T cell stimulation. The Ags to be tested will include (i) the SAG-1 Ag of T. gondii which confers protection in mice when used with adjuvants unacceptable for human use, and (ii) group B streptococcal polysaccharide-tetanus toxoid (TT) conjugates (GBS-TT) which may benefit from additional immunopotentiation. 2) elucidate the parameters for optimal mononuclear phagocyte-targeted Ag presentation, including the valency of targeted Ags with respect to monocyte binding, whether T cell activation in response to targeted Ag can be potentiated further by exogenous cytokines and the mechanism of enhancement via Ag targeting. 3) test the hypothesis that monocyte-targeted Ag is markedly more immunogenic for primary responses in vivo than is non-targeted Ag. A major benefit of targeting may be to enhance primary immune responses in vivo, as a result of specific mononuclear phagocyte activation as well as minimizing the anergy-inducing effects of Ag presentation by resting B cells. We will compare mononuclear phagocyte-targeted preparations of two Ags, GBS polysaccharide-TT and GBS polysaccharide-SAG-1, with non- targeted preparations of two Ags, GBS polysaccharide-TT and GBS polysaccharide-SAG-1, with non-targeted preparations for induction of protective immunity in mice. Overall, these studies will define the parameters for Ag targeting to mononuclear phagocytes that result in the highest efficiency of T cell activation. They will also elucidate the potential of this approach to eliminate the need for toxic adjuvants, and for potentiation of the immune response to vaccines in general.
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