The mucosal lining of the lungs and gastrointestinal tract plays a pivotal role in the detection and elimination of invading pathogens. However, the immune system must be regulated in order to prevent damage to host tissue as dysregulated immune responses may result in severe pathology and subsequent disease. In particular, uncontrolled expansion of T helper (TH) 17 populations has been implicated in numerous inflammatory diseases such as myocarditis, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and asthma. Interleukin (IL)-25 (IL-17E) is a recently described member of the IL-17 cytokine family. Recent studies have demonstrated key functions of IL-25 in TH2 cytokine-mediated host protective immunity and in the inhibition of IL-17-mediated intestinal inflammation. Despite an understanding of its biological relevance, little is known about the functional biology of IL-25. Understanding these regulatory pathways and how they relate to mucosal immunity will better enable the scientific community to develop targeted therapeutics for multiple inflammatory diseases. It has been proposed that IL-25-producing T cells represent a novel T helper cell subset, however, the cellular sources of IL-25 and the phenotypic characteristics of IL-25+ T cells are poor understood. Additionally, the mechanism by which IL-25 inhibits IL-17-mediated intestinal inflammation remains unknown. To address these questions, a murine model of intestinal inflammation, using the gastrointestinal helminth Trichuris muris, will be utilized. Analyses will be performed with a variety of molecular techniques, including flow cytometry, ELISAs, Western blots, and real time PCR. (Millions of people worldwide are affected by autoimmune and inflammatory diseases, such as allergies, asthma, and rheumatoid arthritis. These diseases represent uncontrolled expansion of cells of the immune system. Understanding the regulation of immune responses will impact public health on a global scale.)

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31GM082187-03
Application #
7633319
Study Section
Minority Programs Review Committee (MPRC)
Program Officer
Toliver, Adolphus
Project Start
2007-07-05
Project End
2011-07-04
Budget Start
2009-07-05
Budget End
2010-07-04
Support Year
3
Fiscal Year
2009
Total Cost
$41,176
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Alenghat, Theresa; Osborne, Lisa C; Saenz, Steven A et al. (2013) Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504:153-7
Siracusa, Mark C; Wojno, Elia D Tait; Artis, David (2012) Functional heterogeneity in the basophil cell lineage. Adv Immunol 115:141-59
Siracusa, Mark C; Saenz, Steven A; Hill, David A et al. (2011) TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature 477:229-33
Siracusa, Mark C; Comeau, Michael R; Artis, David (2011) New insights into basophil biology: initiators, regulators, and effectors of type 2 inflammation. Ann N Y Acad Sci 1217:166-77
Hill, David A; Artis, David (2010) Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol 28:623-67
Saenz, Steven A; Siracusa, Mark C; Perrigoue, Jacqueline G et al. (2010) IL25 elicits a multipotent progenitor cell population that promotes T(H)2 cytokine responses. Nature 464:1362-6
Siracusa, Mark C; Perrigoue, Jacqueline G; Comeau, Michael R et al. (2010) New paradigms in basophil development, regulation and function. Immunol Cell Biol 88:275-84
Saenz, Steven A; Noti, Mario; Artis, David (2010) Innate immune cell populations function as initiators and effectors in Th2 cytokine responses. Trends Immunol 31:407-13
Abt, Michael C; Artis, David (2009) The intestinal microbiota in health and disease: the influence of microbial products on immune cell homeostasis. Curr Opin Gastroenterol 25:496-502
Perrigoue, Jacqueline G; Saenz, Steven A; Siracusa, Mark C et al. (2009) MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immunity. Nat Immunol 10:697-705

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