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Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis.

Rayapudi M, Rajavelu P, Zhu X, Kaul A, Niranjan R, Dynda S, Mishra A, Mattner J, Zaidi A, Dutt P, Mishra A - Clin Transl Immunology (2014)

Bottom Line: Herein, we show that iNKT cell number, their receptor subcomponents Vα24 and Vβ11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals.Furthermore, we show that anti-mCD1d- and anti-hVα24Jα18-neutralizing antibody treatment protects allergen-induced experimental EoE.Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Vα24Jα18 antibodies might be a novel and potential therapy for human EoE.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cincinnati , Cincinnati, OH, USA.

ABSTRACT
Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder that needs a potential therapeutic strategy. We earlier showed that iNKT cell-deficient mice are protected from allergen-induced EoE. Therefore, we now tested the hypothesis that iNKT cells are induced in the human EoE and is a novel possible target for the treatment of human EoE. Accordingly, we examine number of iNKT cells and eosinophils and expression of iNKT-associated cell surface receptors and chemokines by performing immunofluorescence, qPCR and ELISA in the esophageal biopsies and blood samples of normal subjects (comparison control) and EoE patients. Herein, we show that iNKT cell number, their receptor subcomponents Vα24 and Vβ11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals. In addition, we show that CXCL16 levels (or expression) correlate with the mRNA levels of Vα24 receptor but not well with esophageal eosinophilia in human EoE. Of note, we show that in vivo activation of iNKT cells is sufficient to induce EoE in mice. Furthermore, we show that anti-mCD1d- and anti-hVα24Jα18-neutralizing antibody treatment protects allergen-induced experimental EoE. Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Vα24Jα18 antibodies might be a novel and potential therapy for human EoE.

No MeSH data available.


Related in: MedlinePlus

Analysis of CXCL16 expression in human esophageal biopsies. A representative photomicrograph of baseline esophageal CXCL16 expression in normal (comparison control) subjects (a, b) and EoE patients (c, d) stained with anti-CXCL16 antibody (a–d) or isotype-matched IgG (e, f) and overlapped with a DAPI-stained mounted reagent. Correlations between the peak eosinophil number/hpf vs CXCL16 mRNA expression and Vα24 vs CXCL16 mRNA expression normalized with GADPH in human EoE (g, h). The r-value was calculated using the Spearman correlation test (n=24–28). Statistical significance was calculated using both the Mann–Whitney and Kruskal–Wallis test.
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fig4: Analysis of CXCL16 expression in human esophageal biopsies. A representative photomicrograph of baseline esophageal CXCL16 expression in normal (comparison control) subjects (a, b) and EoE patients (c, d) stained with anti-CXCL16 antibody (a–d) or isotype-matched IgG (e, f) and overlapped with a DAPI-stained mounted reagent. Correlations between the peak eosinophil number/hpf vs CXCL16 mRNA expression and Vα24 vs CXCL16 mRNA expression normalized with GADPH in human EoE (g, h). The r-value was calculated using the Spearman correlation test (n=24–28). Statistical significance was calculated using both the Mann–Whitney and Kruskal–Wallis test.

Mentions: Murine and human iNKT cells home in the tissue via interaction of receptor CXCR6 and ligand CXCL16;40, 41 therefore, we next examined the source of CXCL16 in the esophageal mucosa by performing rabbit anti-CXCL16 immunofluorescence staining of the esophageal biopsies of comparison control normal subjects and EoE patients. The esophageal mucosa of normal subjects had minimal or undetectable CXCL16 protein expression (Figures 4a and b) compared with esophageal epithelial cells of EoE patient biopsies that had increased expression of CXCL16 protein (Figures 4c and d). The DAPI mounting material stain the cell nucleus and the merged photomicrograph clearly indicated that anti-CXCL16 antibody-stained cells are present in the epithelial mucosa of the biopsies. Esophageal biopsies with isotype-matched IgG (primary anti-CXCL16 antibody is replaced by rabbit IgG isotype matched), the isotype-matched IgG antibody did not show any positive staining in the mucosa of normal or EoE patients (Figures 4e and f). Furthermore, a weak positive correlation was observed with CXCL16 mRNA expression with the mRNA levels of iNKT cell-associated receptor Vα24 and intraepithelial eosinophil counts in the esophageal mucosa of EoE patients (Figures 4g and h). However, the correlation of both the genes was not found statistically significant.


Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis.

Rayapudi M, Rajavelu P, Zhu X, Kaul A, Niranjan R, Dynda S, Mishra A, Mattner J, Zaidi A, Dutt P, Mishra A - Clin Transl Immunology (2014)

Analysis of CXCL16 expression in human esophageal biopsies. A representative photomicrograph of baseline esophageal CXCL16 expression in normal (comparison control) subjects (a, b) and EoE patients (c, d) stained with anti-CXCL16 antibody (a–d) or isotype-matched IgG (e, f) and overlapped with a DAPI-stained mounted reagent. Correlations between the peak eosinophil number/hpf vs CXCL16 mRNA expression and Vα24 vs CXCL16 mRNA expression normalized with GADPH in human EoE (g, h). The r-value was calculated using the Spearman correlation test (n=24–28). Statistical significance was calculated using both the Mann–Whitney and Kruskal–Wallis test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232063&req=5

fig4: Analysis of CXCL16 expression in human esophageal biopsies. A representative photomicrograph of baseline esophageal CXCL16 expression in normal (comparison control) subjects (a, b) and EoE patients (c, d) stained with anti-CXCL16 antibody (a–d) or isotype-matched IgG (e, f) and overlapped with a DAPI-stained mounted reagent. Correlations between the peak eosinophil number/hpf vs CXCL16 mRNA expression and Vα24 vs CXCL16 mRNA expression normalized with GADPH in human EoE (g, h). The r-value was calculated using the Spearman correlation test (n=24–28). Statistical significance was calculated using both the Mann–Whitney and Kruskal–Wallis test.
Mentions: Murine and human iNKT cells home in the tissue via interaction of receptor CXCR6 and ligand CXCL16;40, 41 therefore, we next examined the source of CXCL16 in the esophageal mucosa by performing rabbit anti-CXCL16 immunofluorescence staining of the esophageal biopsies of comparison control normal subjects and EoE patients. The esophageal mucosa of normal subjects had minimal or undetectable CXCL16 protein expression (Figures 4a and b) compared with esophageal epithelial cells of EoE patient biopsies that had increased expression of CXCL16 protein (Figures 4c and d). The DAPI mounting material stain the cell nucleus and the merged photomicrograph clearly indicated that anti-CXCL16 antibody-stained cells are present in the epithelial mucosa of the biopsies. Esophageal biopsies with isotype-matched IgG (primary anti-CXCL16 antibody is replaced by rabbit IgG isotype matched), the isotype-matched IgG antibody did not show any positive staining in the mucosa of normal or EoE patients (Figures 4e and f). Furthermore, a weak positive correlation was observed with CXCL16 mRNA expression with the mRNA levels of iNKT cell-associated receptor Vα24 and intraepithelial eosinophil counts in the esophageal mucosa of EoE patients (Figures 4g and h). However, the correlation of both the genes was not found statistically significant.

Bottom Line: Herein, we show that iNKT cell number, their receptor subcomponents Vα24 and Vβ11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals.Furthermore, we show that anti-mCD1d- and anti-hVα24Jα18-neutralizing antibody treatment protects allergen-induced experimental EoE.Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Vα24Jα18 antibodies might be a novel and potential therapy for human EoE.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cincinnati , Cincinnati, OH, USA.

ABSTRACT
Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder that needs a potential therapeutic strategy. We earlier showed that iNKT cell-deficient mice are protected from allergen-induced EoE. Therefore, we now tested the hypothesis that iNKT cells are induced in the human EoE and is a novel possible target for the treatment of human EoE. Accordingly, we examine number of iNKT cells and eosinophils and expression of iNKT-associated cell surface receptors and chemokines by performing immunofluorescence, qPCR and ELISA in the esophageal biopsies and blood samples of normal subjects (comparison control) and EoE patients. Herein, we show that iNKT cell number, their receptor subcomponents Vα24 and Vβ11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals. In addition, we show that CXCL16 levels (or expression) correlate with the mRNA levels of Vα24 receptor but not well with esophageal eosinophilia in human EoE. Of note, we show that in vivo activation of iNKT cells is sufficient to induce EoE in mice. Furthermore, we show that anti-mCD1d- and anti-hVα24Jα18-neutralizing antibody treatment protects allergen-induced experimental EoE. Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Vα24Jα18 antibodies might be a novel and potential therapy for human EoE.

No MeSH data available.


Related in: MedlinePlus