Benaroya Research Institute
Benaroya Research Institute at Virginia Mason1201 9th AveSeattle, WA 98101
The laboratory is interested in the underlying mechanisms that control the development and function of the immune system. The lab works on two areas:
FoxP3 and the control of CD4+CD25+ regulatory T cell development and function. The forkhead-family transcription factor FoxP3 has been implicated in the development and function of CD4+CD25+ regulatory T cells (Tregs). In the mouse, FoxP3 expression is both necessary and sufficient for generating Tregs, while FoxP3 expression has been shown to correlate with Treg function in humans. My laboratory is taking several approaches to better understand the role of this protein: 1. Structure/function analysis of FoxP3. 2. Consequences of ectopic FoxP3 expression. 3. Treg/Th17 differentiation.
TSLP and allergic inflammation. We are also studying a cytokine called thymic stromal lymphopoietin (TSLP). TSLP is an IL-7-like cytokine that is expressed by epithelial cells in the lung, skin, and gut. Recent work has shown that TSLP can stimulate a wide variety of hematopoietically-derived cells, including dendritic cells, macrophages, CD4 T cells and B cells. Our lab has shown that TSLP responses are absolutely required for the development of Th2-type immunity in mice. In support of its role in allergic inflammation, keratinocytes from patients with atopic dermatitis produce high levels of TSLP, while keratinocytes from normal individuals do not. We have modeled human allergic diseases using transgenic mice that express TSLP at specific sites. Thus far we have mice that express an inducible TSLP transgenes in the skin and lungs. In both cases the mice develop the corresponding disease when the transgene is expressed-atopic dermatitis in the skin and asthma in the lung. We have also shown that TSLP is absolutely required for antigen-induced asthma in the mouse, demonstrating that this cytokine is both necessary and sufficient for allergic asthma. We have begun to analyze human patients with a variety of pulmonary inflammation diseases and have found TSLP to be at elevated levels. TSLP blockade is now being evaluated as a therapeutic tool in these diseases. Current studies include an analysis of the regulation of TSLP gene expression, signal transduction from the TSLP receptor, and the identification and characterization of downstream mediators of TSLP-mediated inflammation. We are also using model systems to understand the role of TSLP in allergic disease and in respiratory virus infection.
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Fred Hutch | University of Washington
Institute for Systems Biology (ISB)| Center for Infectious Disease Research