This proposal is a renewal application of the revised R01 grant funded for two years under the NIH American Recovery Reinvestment Act (ARRA). This grant, funded from July 15, 2009 to June 30, 2011, has led to elucidation of a series of fundamental principles concerning the role of IL-15 in EE pathogenesis. This renewal application seeks to extend our basic and translational analysis of EE, aimed at uncovering the role of IL-15 and IL-15-responsive cells in the regulation of esophageal eosinophilia in human EE. In the first cycle of this two-year R01 grant, we identified several key molecules that are directly responsible for the initiation and progression of EE pathogenesis in experimental models and have developed evidence that these findings apply to human EE. The details of our findings are presented in the progress report. In brief, we have demonstrated induced IL-15 mRNA/protein and iNKT cells in the esophageal biopsies of human EE and provided evidence that IL-15 and iNKT cells have a critical role in the initiation and progression of aeroallergen- o food allergen (peanut)-induced experimental EE. Therefore, in the extended cycle of grant tenure, we propose to test the central hypothesis that chronic IL-15 expression leads to the development of IgE- associated EE pathogenesis and that receptors, chemokines, and surface molecules of IL-15- responsive cells are the potential diagnostic and therapeutic targets molecules for human EE. The three specific aims will test our central hypothesis. In the first aim,we will test several sub-hypotheses concerning the role of IL-15 in the induction of mast cells; B cell growth, activation, and proliferation; and the mechanism of Ig class switching in EE by examining the esophageal transcript profile of IL-15 overexpression mice. Correlation of IL-15 with the presence of esophageal furrows, rings, and stricture in human EE will also be examined.
The second aim will test the hypothesis that IL-15 and cell surface molecules and chemokines of IL-15-responsive cells may be novel diagnostic biomarkers for human EE. We will test several related sub- hypotheses concerning the mRNA and protein levels of IL-15, IL-15R , IgE, CD1d, V 24, and CXCL16 in the blood of normal individuals and patients with gastroesophageal reflux disease (GERD) and EE. In the third aim, we propose a set of experiments designed to test several related primary hypotheses focused around iNKT cells and IL-15 being novel target molecules for EE therapy. Our studies are timely given the recent attention that EE is receiving in the medical community.
Eosinophilic esophagitis is a recently recognized inflammatory esophageal disorder. While it is being increasingly diagnosed; the etiology of the disease pathogenesis is not yet clearly understood. The goal of the present proposal is to investigate a novel mechanistic pathway based on IL-15 overexpression and induction of IL-15-responsive cells in the esophagus in order to provide a better understanding of EE and novel diagnostic biomarkers and therapeutic target molecules for human EE.
|Venkateshaiah, Sathisha Upparahalli; Manohar, Murli; Verma, Alok K et al. (2016) Possible Noninvasive Biomarker of Eosinophilic Esophagitis: Clinical and Experimental Evidence. Case Rep Gastroenterol 10:685-692|
|Sanders, Nathan L; Mishra, Anil (2016) Role of interleukin-18 in the pathophysiology of allergic diseases. Cytokine Growth Factor Rev 32:31-39|
|Dutt, Parmesh; Shukla, Jai Shankar; Ventateshaiah, Sathisha Upparahalli et al. (2015) Allergen-induced interleukin-18 promotes experimental eosinophilic oesophagitis in mice. Immunol Cell Biol 93:849-57|
|Niranjan, Rituraj; Rajavelu, Priya; Ventateshaiah, Sathisha Upparahalli et al. (2015) Involvement of interleukin-18 in the pathogenesis of human eosinophilic esophagitis. Clin Immunol 157:103-13|
|Zaidi, Asifa K; Mussarat, Ahad; Mishra, Anil (2014) Diagnostic and therapeutic strategies for eosinophilic esophagitis. Clin Pract (Lond) 11:351-367|
|Mavi, Parm; Niranjan, Rituraj; Dutt, Parmesh et al. (2014) Allergen-induced resistin-like molecule-Î± promotes esophageal epithelial cell hyperplasia in eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 307:G499-507|
|Rayapudi, Madhavi; Rajavelu, Priya; Zhu, Xiang et al. (2014) Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis. Clin Transl Immunology 3:e9|
|Niranjan, Rituraj; Rayapudi, Madhavi; Mishra, Akanksha et al. (2013) Pathogenesis of allergen-induced eosinophilic esophagitis is independent of interleukin (IL)-13. Immunol Cell Biol 91:408-15|
|Niranjan, Rituraj; Mavi, Parm; Rayapudi, Madhavi et al. (2013) Pathogenic role of mast cells in experimental eosinophilic esophagitis. Am J Physiol Gastrointest Liver Physiol 304:G1087-94|
|Mishra, Anil (2013) Significance of Mouse Models in Dissecting the Mechanism of Human Eosinophilic Gastrointestinal Diseases (EGID). J Gastroenterol Hepatol Res 2:845-853|
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