Celiac disease is a complex intestinal inflammatory disorder with villous atrophy induced by dietary gluten in HLA-DQ2 or HLA-DQ8 individuals. The disease is the 'tip of an iceberg'including a larger subclinical population with various aspects of dysregulation in response to gluten. Immunological abnormalities associated with gluten uptake include (1) chronic upregulation of IL-15 in the epithelium and lamina propria, (2) massive expansion of natural killer-like intraepithelial cytotoxic lymphocytes (IE-CTL), (3) DQ2 or DQ8-restricted anti- gluten CD4 T cells secreting IFNg? in the lamina propria and (4) signature antibodies against gluten and the tissue transglutaminase (TTG) that binds and deamidates gluten. Villous atrophy may depend on the anti- gluten IFNg?+ CD4 T cell response, the expansion of IE-CTL and the overexpression of IL-15, but the precise links between these effector mechanisms remain unclear. The overarching aim of this proposal will be to model and investigate in vivo the consequences of chronic IL-15 expression using established transgenic systems expressing IL-15 at levels comparable to those observed in disease, and dissecting expression in the intestinal epithelium (villin promoter, V-IL15tg) and outside the epithelium in the lamina propria DC (minimal MHC class I Dd promoter, Dd-IL15tg). The conclusions will then be tested against a cohort of relatives of celiac patients where these immunological abnormalities naturally segregate. The ultimate goal is to combine DQ8 and IL-15 to model the histopathological stages of celiac disease.
Specific aim 1, will analyze the impact of IL-15 on the breakdown of oral tolerance to ingested gluten;
Specific Aim 2 will analyze the role of IL-15 in the acquisition of a natural killer phenotype by intraepithelial lymphocytes and the development of villous atrophy;
and Specific Aim 3, will analyze in human studies the link between IL-15, anti-gluten adaptive immunity and natural killer transformation of intraepithelial lymphocytes. Collectively, these studies will not only provide new insights into the pathogenesis of celiac disease and the major impact of dysregulated IL-15 expression but also, importantly, will guide and refine new generation animal models. Because a strict lifelong gluten-free diet imposes tremendous constraints on patients, such models are long overdue to test alternative therapies that will be developed in the near future.

Public Health Relevance

Celiac Disease is an intestinal inflammatory intestinal disorder with a high prevalence (>1%), that is induced by dietary gluten. Understanding how different components of the immune system contribute to disease and developing a mouse model of celiac disease will have a major impact on our understanding of the disease, and the treatment and follow-up of celiac disease patients. PROJECT NARRATIVE Celiac Disease is an intestinal inflammatory intestinal disorder with a high prevalence (>1%), that is induced by dietary gluten. Understanding how different components of the immune system contribute to disease and developing a mouse model of celiac disease will have a major impact on our understanding of the disease, and the treatment and follow-up of celiac disease patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067180-10
Application #
8727526
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Perrin, Peter J
Project Start
2004-04-01
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
Bunker, Jeffrey J; Flynn, Theodore M; Koval, Jason C et al. (2015) Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A. Immunity 43:541-53
Setty, Mala; Discepolo, Valentina; Abadie, Valérie et al. (2015) Distinct and Synergistic Contributions of Epithelial Stress and Adaptive Immunity to Functions of Intraepithelial Killer Cells and Active Celiac Disease. Gastroenterology 149:681-91.e10
Tang, Fangming; Sally, Benjamin; Lesko, Kathryn et al. (2015) Cysteinyl leukotrienes mediate lymphokine killer activity induced by NKG2D and IL-15 in cytotoxic T cells during celiac disease. J Exp Med 212:1487-95
Kim, Sangman Michael; Mayassi, Toufic; Jabri, Bana (2015) Innate immunity: actuating the gears of celiac disease pathogenesis. Best Pract Res Clin Gastroenterol 29:425-35
Jabri, Bana; Abadie, Valérie (2015) IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol 15:771-83
Verdu, Elena F; Galipeau, Heather J; Jabri, Bana (2015) Novel players in coeliac disease pathogenesis: role of the gut microbiota. Nat Rev Gastroenterol Hepatol 12:497-506
McDonald, Benjamin D; Bunker, Jeffrey J; Ishizuka, Isabel E et al. (2014) Elevated T cell receptor signaling identifies a thymic precursor to the TCRαβ(+)CD4(-)CD8β(-) intraepithelial lymphocyte lineage. Immunity 41:219-29
Orbelyan, Gerasim A; Tang, Fangming; Sally, Benjamin et al. (2014) Human NKG2E is expressed and forms an intracytoplasmic complex with CD94 and DAP12. J Immunol 193:610-6
Abadie, Valérie; Jabri, Bana (2014) IL-15: a central regulator of celiac disease immunopathology. Immunol Rev 260:221-34
Liu, Rebecca Berlant; Engels, Boris; Schreiber, Karin et al. (2013) IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc Natl Acad Sci U S A 110:8158-63

Showing the most recent 10 out of 24 publications