Parasitic helminths elicit host immune responses characterized by infiltration of tissues vi/ith Th2 cells,basophils and eosinophils, and the generation of high IgE in serum. These responses reflect stereotypedhost mucosal and systemic immunity orchestrated by Th2 cells. Through elaboration of IL-4 and IL-13, Th2cells organize a focused response necessary to mediate the physiologic alterations ofthe epithelial ban-ier,including enhanced mucus secretion and epithelial cell turnover. Despite these observations, the precisecells which elaborate the IL-4 and IL-13 required to mediate immunity are unknown, and how these cellsmight contribute to the pathology associated with chronic infestations is poorly understood. We havegenetically marked cells that produce IL-4 and, in the last year, IL-13, in the mouse, thus allowing us tofollow the cells that contribute these functionally important cytokines. Using infection with Nippostrongylusbrasiliensis as well as other challenges, we have begun a systematic dissection ofthe cells and cytokinesinvolved, and of how these cells interact in the relevant tissues. We have managed to generate cell-conditional deletion of IL-4 and IL-13 in important cytokine-producing cells in both the innate and adaptiveimmune systems. We have also managed conditional deletion of important innate and adaptive cells,including the first demonstration of a basophil-deficient mouse. With these reagents in hand, we are wellpoised to complete the specific aims of this grant, which remain to use cytokine-function marking todetermine (1) which cells are the critical sources of IL-4 and IL-13 in mediating intestinal helminth immunity;(2) which cell types are critical in mediating intestinal helminth immunity; and (3) what is the physicalorganization of these critical cells and cytokines in tissue that is required to sustain functional Th2-associatedimmune responses in tissues. These findings will contribute significantly to our understanding of this poorlyunderstood but universal immune response, which is shared by human responses to widely endemicparasitic worms, but also by allergic reactions underlying atopy and asthma.

Public Health Relevance

Parasitic helminth infections plague billions of persons worldwide and our understanding ofthe host immuneresponse is only rudimentary. Helminthes are vertebrate pathogens and these immune responses can onlybe understood in the context of the host. Unraveling the pathways involved has great potential to controlimmune responses not only to helminthes, but also to allergens, which share these types of immunity, withthe potential for controlling or treating many important diseases of humans.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Wali, Tonu M
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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