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Abstract
This thesis focuses on modulating the innate immune responses with chemical tools with two specific goals: (1) to improve vaccines by determining the best way to elicit immune signaling from the cells with the strongest signaling capability and (2) to better understand the biological mechanisms that lead to allergic contact dermatitis and provide potential therapeutics to treat this condition. Vaccines are one of the best ways to prevent disease in humans and animals; by this prevention of disease, vaccines extend survival and improve quality of life. Vaccines work by educating the immune system to recognize a particular pathogen without risk of getting the disease. Vaccines rely on antigen presenting cells to signal to adaptive immune cells to generate a robust and specific protective response. In this work, I isolate and characterize first-responding dendritic cells (FRs), a subset of dendritic cells that (1) show increased responses to pathogen associated molecular patterns, (2) facilitate adaptive immune responses by providing the initial paracrine signaling, and (3) can be selectively targeted by vaccines to modulate both antibody and T cell responses in vivo. Additionally, by targeting the FRs with a synergistic TLR agonist formulation, we demonstrate that we can enhance the FR cytokine response for TNF-α, IL-6, and IL12-p70. Additionally, we reduce bulk population cytokines using a brefeldin loaded liposome that selectively targets FRs, ablating their signaling function. These results demonstrate the importance of FRs in generating large scale immune responses necessary to provide robust antibody protection against disease, and how these FRs can be targeted by vaccines to optimize results.Allergic contact dermatitis (ACD) is a condition in which an individual has an inflammatory response to small compounds called contact allergens. ACD is estimated to affect up to 20 % of the USA’s population and is characterized by a sensitization phase and elicitation phase. ACD is the most common occupational hazard in the United States, resulting in millions of dollars of productivity loss per year. In this work, we identify honokiol as the first known compound to reduce both sensitization and elicitation to dinitrochlorobenzene, a model hapten. Additionally, we identify IRF-3 is a key inflammatory transcription factor in the ACD response. These findings promise to enable novel classes of therapeutics for ACD.