The long-term objective of this proposal is to analyze the molecular mechanisms of host immune exploitation by skin-stage schistosomula of S. mansoni. Through preliminary studies we identified two molecules in the secretions of skin-stage schistosomula that modulate immune function in the skin. One of these molecules affects migration of dendritic cells (DCs) from the skin; a phenomenon that is important in the initiation of immune response and the other molecule is a pro-apoptotic factor for T cells in the skin and skin draining lymph nodes. Therefore, these two molecules appear to act independently but in a similar fashion impairing the development of initial cellular immune responses to this parasite in the skin. The pro-apoptotic molecule (Sm22) was subsequently cloned and partially characterized. These studies showed that Sm22 is a potent apoptosis-inducing molecule for T cells in the skin. Specific aim 1 will focus on further characterizing this molecule and identifying the potential mechanisms by which Sm22 induce apoptosis of T cells. These studies will also attempt to identify the pro-apoptotic domain of this molecule and evaluate the effect of neutralizing the activity of this molecule on the immune response to this parasite in the skin. Specific aim 2 will purify the DC modulating 12 kDa molecule, clone its gene, prepare recombinant Sm12 and analyze in detail the migration inhibition function of the molecule on DCs. Specific aim 3 will evaluate the effect of neutralizing the activity of these two molecules on the generation of immune response to this parasite in the skin. Thus, the specific aims of this proposal in general can be summarized as an approach to study the molecular mechanisms by which the skin-stage schistosomula of S. mansoni evade host immune responses. Results from these findings may help (a) understand events surrounding the initiation of immune response and (b) possibly delineate the role of T cells and DCs in immunity against schistosomiasis. Overall, the findings from these studies we believe might help improve per-cutaneous vaccination against this disease using defined candidate vaccine antigens against schistosomiasis.