Assistant Professor: Department of Pediatrics
Staff Scientist: Benaroya Research Institute at Virginia Mason, Seattle, WA
Postdoctoral Fellowships : Benaroya Research Institute at Virginia Mason, Seattle, WA
PhD: University of Washington, Seattle, WA
E-mail: zhoub@iupui.edu

Current Research Interests:
Molecular and cellular regulation of Type II (T helper 2, Th2) immunity and development of allergy. Pathogenesis of atopic diseases with focus on identifying therapeutic targets.

Research:
Atopic diseases consist of the triad of asthma, allergic rhinitis, and atopic dermatitis. The incidence of atopic diseases has more than doubled in Western countries in the last two decades. These allergic diseases have in common an inflammatory Th2 response to allergen but still remain poorly understood and difficult to manage. Recent studies suggest that the cytokine thymic stromal lymphopoietin (TSLP) is a key factor involved in initiation of the Th2 response in allergic inflammation. Firstly, TSLP expression is found to correlate with allergic disease in both human patients and animal models. Its levels are increased in asthmatic airways and lesional skin of atopic dermatitis patients. Secondly, TSLP, acting on CD11c+ dendritic cells (DCs), is able to prime naïve CD4+ T cells to differentiate into Th2 cells. Lastly, we demonstrated that TSLP is both necessary and sufficient for asthma-like airway inflammatory disease in mice. Airway inflammation in an antigen-induced mouse model of asthma is greatly attenuated in TSLP receptor-deficient mice, while mice that express a lung-specific TSLP transgene develop an airway inflammatory disease with all the cardinal features of human asthma. Even with recent work, however, important questions as to the regulation of TSLP expression and the nature of the cells and factors downstream remain to be addressed.

Ongoing Projects:
1) Molecular and cellular regulation of TSLP expression. We have demonstrated that TSLP plays important roles in both primary immune responses (allergic sensitization) and secondary immune responses (allergy elicitation). However, the source of TSLP and factors upregulating it in these processes remain to be defined. To answer these questions, we developed a TSLP reporter mouse line in which endogenous TSLP expression is tracked by a red fluorescent protein (RFP). The mouse line will be very useful in delineating the magnitude and compartmentalization of TSLP expression at critical stages to better understand its role in normal immune system development and allergic disease pathogenesis.
2) Targets downstream of TSLP. DCs play a crucial role in immune regulation by directing adaptive immunity to an optimal response against insult such as tolerance vs immunity, or Th1 vs Th2 differentiation. In vitro studies have demonstrated that TSLP-activated DCs are capable of promoting Th2 differentiation and maintaining Th2 central memory. On the other hand, it has been suggested that TSLP can act directly on CD4+ T cells to promote Th2 cytokine expression. We will use bone marrow chimera and adoptive transfer techniques to explore the relative contribution of DCs and CD4+ T cells downstream of TSLP toward the pathogenesis of asthma. Phenotypic differences of the cells with or without intact TSLP receptor will also be studied.
3) Exploring TSLP as a therapeutic target for asthma. Our finding that TSLP is both necessary and sufficient for the development of allergic airway inflammation suggests that blockade of TSLP could be a novel treatment for asthma and other allergic diseases. We have demonstrated that neutralization of TSLP significantly reduces airway inflammation in an acute asthma model and will further test if TSLP is needed to maintain the airway inflammation seen in chronic asthma models.

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