Esophageal eosinophilia has a strong association with T helper type 2 (Th2) allergic responses and occurs in a variety of states including eosinophilic esophagitis (EE). Recently, we made a novel observation that local induction of Th2 cytokines, eosinophils and T cells are critical in the pathogenesis of EE. Despite these efforts and findings, we are still unable to target specific cell types, chemokine or cytokine for therapeutic intervention strategy for the treatment of EE. In order to further provide insight into the molecular and cellular mechanisms of EE pathogenesis, we now focus our attention to investigate the role of IL-15 and iNKT cells in EE pathogenesis. The rationale behind understanding their role in EE is, i) IL-15 and iNKT cell associated genes are induced in both experimental and human EE;ii) IL-15 is produced by a number of inflammatory cells including dendritic cells and epithelial cells;iii) IL-15 is required for the development of naove and memory CD8 T cells, intestinal intraepithelial lymphocytes (IEL), NK and iNKT cell lineages;and iv) IL-15 and iNKT cells are implicated in a broad range of autoimmune and allergic diseases but has not previously been studies in EE. In this grant proposal, the PI proposes to test the hypothesis that the pathogenesis of EE involves IL-15-induced iNKT cell-mediated inflammation. We propose three aims designed to test the role of IL-15 in experimental and human EE. In the first aim, we will examine the critical role of IL-15 in the induction of EE.
The second aim will be focused on the mechanism of iNKT cell esophageal homing, activation, and the role in EE pathogenesis. In the third aim, we will translate our pre-clinical observations into the human EE by examining the levels of IL-15, iNKT cells and their related homing and activation molecules in normal individuals and EE patients, and analyzing their correlations with the esophageal eosinophilia. Our studies are timely given the recent attention that EE is receiving in the medical community. Eosinophilic esophagitis (EE) is a worldwide growing medical problem;however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to identify a target molecule for EE therapy by examining the role of IL-15 and iNKT cells in the pathogenesis of EE.

Public Health Relevance

Eosinophilic esophagitis (EE) is a worldwide growing medical problem;however, the etiology of the disease pathogenesis is not well understood. The goal of our proposed study is to identify a target molecule for EE therapy by examining the role of IL-15 and iNKT cells in the pathogenesis of EE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI080581-01
Application #
7560476
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Plaut, Marshall
Project Start
2009-07-22
Project End
2011-06-30
Budget Start
2009-07-22
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$371,814
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Mussarat, Ahad; Manohar, Murli; Verma, Alok K et al. (2018) Intestinal overexpression of interleukin (IL)-15 promotes tissue eosinophilia and goblet cell hyperplasia. Immunol Cell Biol 96:273-283
Sandersa, Nathan L; Venkateshaiah, Sathisha Upparahalli; Manohar, Murli et al. (2018) Interleukin-18 has an Important Role in Differentiation and Maturation of Mucosal Mast Cells. J Mucosal Immunol Res 2:
Venkateshaiah, Sathisha Upparahalli; Zhu, Xiang; Rajavelu, Priya et al. (2018) Regulatory effects of IL-15 on allergen-induced airway obstruction. J Allergy Clin Immunol 141:906-917.e6
Manohar, Murli; Verma, Alok K; Venkateshaiah, Sathisha Upparahalli et al. (2018) Role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Am J Physiol Gastrointest Liver Physiol 314:G211-G222
Venkateshaiah, Sathisha Upparahalli; Mishra, Akanksha; Manohar, Murli et al. (2018) A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils. J Allergy Clin Immunol 142:301-305
Verma, Alok K; Manohar, Murli; Venkateshaiah, Sathisha Upparahalli et al. (2018) Role of Vasoactive Intestinal Peptide in Promoting the Pathogenesis of Eosinophilic Esophagitis (EoE). Cell Mol Gastroenterol Hepatol 5:99-100.e7
Manohar, Murli; Verma, Alok Kumar; Venkateshaiah, Sathisha Upparahalli et al. (2017) Pathogenic mechanisms of pancreatitis. World J Gastrointest Pharmacol Ther 8:10-25
Manohar, Murli; Verma, Alok K; Upparahalli Venkateshaiah, Sathisha et al. (2017) Food-Induced Acute Pancreatitis. Dig Dis Sci 62:3287-3297
Verma, Alok K; Manohar, Murli; Upparahalli Venkateshaiah, Sathisha et al. (2017) Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases. Cytokine Growth Factor Rev 38:37-48
Manohar, Murli; Verma, Alok K; Venkateshaiah, Sathisha Upparahalli et al. (2017) Chronic Pancreatitis Associated Acute Respiratory Failure. MOJ Immunol 5:

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