Mucosal Immunology Laboratory, Director: W. Allan Walker
Summary of Research
My research is focused on the pathogenesis and immune regulation of intestinal inflammation. We are particularly interested in exploring the mechanisms by which the helminth parasite modulates intestinal mucosal response to enteric bacteria and bacteria-associated intestinal inflammation using a co-infection model system. This system involves two murine enteric infectious agents that induce distinct Th responses: (i) the helminth Heligmosomoides polygyrus (Th2) and (ii) the Gram-negative bacterium Citrobacter rodentium (Th1). The distribution of several pathogenic helminth infections coincides geographically with many devastating microbial diseases, such as HIV, malaria, tuberculosis and EPEC and EHEC. Evidence from epidemiological studies indicates an inverse correlation between exposure to helminths and the incidence of certain immune-mediated diseases (the hygiene hypothesis), including inflammatory bowel diseases (IBD). A more comprehensive understanding of immunoregulation in the intestinal mucosa may provide new information for establishing more effective preventive and therapeutic approaches to the treatment of both Th1 and Th2-mediated diseases, and for the design of effective intestinal vaccines.
The intestinal tract harbors the largest concentration and diversity of bacterial antigens in the body. It is extremely important for the intestinal epithelial cells and the intestinal mucosal immune system to discriminate between pathogenic and non-pathogenic bacteria and to generate an appropriate response, maintaining a state of homeostasis with the normal microbial flora or initiating inflammatory responses to pathogens. Our research also examines and defines the conditions under which dysregulation of intestinal mucosal response to luminal antigen triggers the development of an intestinal inflammatory response that results ultimately in chronic intestinal inflammatory disease, using both in vivo and in vitro approaches. Specifically, we explore the role of bacterial products as triggering agents to alter intestinal barrier function and mucosal immune function. We also study the impact of intestinal colonization of probiotics at early life on the development and regulation of mucosal T cell responses (Th1, Th2 and T regs) and explore the mechanisms by which probiotics modulate host protection against enteric pathogens. Our research will provide greater insight about how intestinal microorganisms may alter the regulatory mechanisms of mucosal immunity, which may be instrumental in the establishment of effective preventive and therapeutic approaches for the treatment of immune mediated disorders.
Contact Information
Phone: 617-726-4173
Fax: 617-726-4172
E-mail: hshi1@partners.org
