Stat6 in Atopic Dermatitis

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Atopic dermatitis (AD) is a common manifestation of the allergic phenotype. Characterized by erythema, pruritis, swelling and hives, Atopic Dermatitis can be an early indicator of subsequent atopic phenotypes. At least half of infants diagnosed with Atopic Dermatitis will develop subsequent atopic disease, such as eosinophillic esophagitis, food allergy, allergic rhinitis and allergic asthma. However, the pathogenesis of Atopic Dermatitis and the contribution of this condition to subsequent allergic phenotypes are still largely unclear. Th2 cells, T cells that secrete IL-4, IL-5, IL-13 and other cytokines are critical in the development of atopic diseases. IL-4 promotes the development of Th2 cells by activation of the Signal Transducer and Activator of Transcription State. Mice deficient in State have a general decrease in Th2 immunity and in models of asthma and eosinophilic esophagitis have greatly diminished disease. Increased levels of Th2 responses are often associated with the development of Atopic Dermatitis. However, the lack of a model of Atopic Dermatitis that is strictly dependent upon Th2 immunity has hampered a more detailed analysis of Th2 cells in AD. We have recently developed transgenic mice expressing a constitutively active State (Stat6VT) in T cells resulting in a hyper-Th2 phenotype. These mice are prone towards developing an Atopic Dermatitis phenotype in a specific pathogen free environment. Moreover, Stat6VT transgenic mice on an IL-4-deficient background do not develop disease, supporting the requirement forTh2 immunity in this model. The overall goal of this project is to determine the role of Th2 effector cytokines in a model of Atopic Dermatitis and determine how, in both patient samples and in our mouse model, Atopic Dermatitis pathogenesis affects immune responses and might contribute towards the development of subsequent atopic diseases. Our hypothesis is that a Th2 skewed immune response is predisposed towards atopic dermatitis and increases the risk of subsequent allergic responses. This will be tested in three Aims: 1, Define cytokine secretion and State activation in specific T cell populations from infants with Atopic Dermatitis; 2, Define the effectors required for the development of Atopic Dermatitis in StatBVT transgenic mice; and 3, Define the role of Atopic Dermatitis in predisposition towards subsequent atopic diseases using animal models. The results of these Aims will better define the role of Th cells in the generation of Atopic Dermatitis and subsequent allergic diseases.