The skin is the largest organ of the human body and represents the body's primary interface with the external environment. As such, the skin is challenged by a broad range of factors and conditions. These include both endogenous (genetic, immunologic, and systemic) and exogenous (solar radiation, allergens, irritants, pollutants, and microbes) factors. As a result, the skin is a major site for disease including inflammation and cancer. Dendritic cells are immune cells that begin and coordinate immune responses. The skin is one of the largest repositories of these dendritic cells. Thus, in addition to being a direct target for inflammation, the skin is one of the prime sites where systemic immune responses begin. The proposed program includes four primary themes. The first three themes revolve around the use of the skin immune system (and skin dendritic cells) to modify immune responses (The skin immune system in the induction of immune responses; The skin immune system in the reduction of immune responses and; The skin immune system in disease pathogenesis). The final theme involves the use of pharmaceutical agents to modulate the activity of nonskin derived dendritic cells. The skin offers a unique opportunity to observe and manipulate dendritic cells and thereby the immune system. The focus on the skin as an organ to manipulate immune responses is innovative. This program will lead to a better understanding of the role of the skin immune system in systemic as well as local autoimmune disease (examples include lupus, psoriasis and type 1 diabetes). Further, the program will lead to cost effective strategies to treat and prevent human disease with anticipated improvements in vaccine delivery and efficacy and novel methods to control autoimmune disease.