This proposal seeks to understand the role of chitin in activating allergic-type immunity in living animals. Chitin is a natural constituent of many organisms, including Crustacea, insects, fungi and worms, that have been associated with allergic-like immune responses in humans. Such immune responses contribute a large and increasing health care burden to the country, and are particularly prevalent in children. Recently, we have established that chitin can activate innate infiltration of tissues with allergy-associated cells, including eosinophils, basophils and alternatively activated macrophages. This grant will seek to characterize the kinetics of this response and the role of chitin in modulating signals from prevalent microbial constituents, such as LPS, and will use a physiologic infection with the model helminth, Nippostrongylus brasiliensis. The key experimental strategy builds on the use of reporter mice with markers inserted into critical genes implicated in these types of immune responses. In turn, collaboration with each of the investigators on this PPG will be used to create mice in which classic inflammatory signals are modulated negatively or positively, thus testing the hypothesis that immune responses to chitin may serve to dampen inflammatory responses at mucosal barriers. This will be tested in 3 specific aims that will address the induction of the allergic immune response, the capacity to induce adaptive Th2-associated responses through activation of dendritic cells, and the modulation afforded by induction of mucosal chitinase, which degrades the chitin signal, and cytokines such as TSLP that may positively regulate the response. The major investigative modalities will be multiparameter flow cytometry that allows precise correlation of cell types with functions, together with immunohistochemistry approaches that facilitate insights towards cell positioning. This two modalities will be supported as core facilities in this Program Project. Achievement of these aims will greatly facilitate our understanding of the genesis of allergic immunity, and potentially suggest novel therapeutic strategies in allergic immunity, helminth immunity and in creating new adjuvants targeting mucosal immune responses. (LAY) Allergic immunity is an increasing problem in developed countries, including the United States. Almost nothing is known about how these types of immune responses are inititated by various environmental insults. This grant will examine how chitin, a constituent of worms, shellfish, molds and insects, all of which have been associated with human allergy, induces allergic immune responses in model animal worm infections. Such insights may contribute to new methods for control of these immune reactions.
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