The aim of these efforts were to establish mouse models as outlined in the objectives for the study of the role of mast cells in regulating the immune response and autoimmune disease as well as to being analysis of T cell-mast cell interactions. Results: The objectives of the past year were met in the following manner. We established five separate models for studying the role of mast cells in immunity and autoimmunity. These mouse models will allow us to test the importance of mast cells, IgE, and IL-4 in the systemic lupus-like disease observed in Lyn-deficient mice. In addition, we have successfully established a model of PTEN-deficiency, which results in severe disease including a striking skin disease with massive mast cell infiltration and inflammation of the bowel. We are also generating mice that should provide useful in models of rheumatoid arthritis. Additionally, we initiated studies to explore the effects of regulatory T cells on mast cells and vice versa. These studies reveal that, while mast cells can cause regulatory T cell expansion, regulatory T cells through OX40 interactions with OX40L on the mast cell surface cause suppression of mast cell degranulation by affecting calcium fluxes. These initial findings prompt the development of new models to address the importance of these interactions in vivo. Conclusions and Significance: In summary, while this project is in its early stages we believe it holds promise for understanding the role of mast cells in the immune system as initiators and regulators of inflammation. It is expected that this information would provide new strategies with therapeutic benefit in inflammatory disease.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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Hershko, Alon Y; Charles, Nicolas; Olivera, Ana et al. (2012) Cutting edge: persistence of increased mast cell numbers in tissues links dermatitis to enhanced airway disease in a mouse model of atopy. J Immunol 188:531-5
Hershko, Alon Y; Suzuki, Ryo; Charles, Nicolas et al. (2011) Mast cell interleukin-2 production contributes to suppression of chronic allergic dermatitis. Immunity 35:562-71
Sibilano, Riccardo; Gri, Giorgia; Frossi, Barbara et al. (2011) Technical advance: soluble OX40 molecule mimics regulatory T cell modulatory activity on Fc?RI-dependent mast cell degranulation. J Leukoc Biol 90:831-8
Charles, Nicolas; Rivera, Juan (2011) Basophils and autoreactive IgE in the pathogenesis of systemic lupus erythematosus. Curr Allergy Asthma Rep 11:378-87
Watford, Wendy T; Wang, Chun-Chi; Tsatsanis, Christos et al. (2010) Ablation of tumor progression locus 2 promotes a type 2 Th cell response in Ovalbumin-immunized mice. J Immunol 184:105-13
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Gri, Giorgia; Piconese, Silvia; Frossi, Barbara et al. (2008) CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 29:771-81