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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

In vivo iNKT cell activation by PBS57 and esophageal eosinophil analysis. Mice (BALB/c) were exposed to repeated exposure of intravenous (i.v.) or intranasal (i.n.) PBS57  as per the protocol shown in (a). After 20–24 h of the last PBS57 or vehicle challenge, mice were killed, and eosinophil levels were evaluated in the esophagus (b) and BALF (c). Representative anti-MBP antibody-immunostained high-resolution photomicrographs of intraepithelial eosinophils in the esophagus after vehicle (d, original magnification × 100) or intranasal PBS57 challenge (e, original magnification × 100 and f, original magnification × 400). The absolute numbers of eosinophils in the esophagus of CD1d- mice and wild-type mice after intranasal PBS57 challenge of mice (g). Data are expressed as mean±s.d., n=12 mice/group. EP, epithelium; LP, lamina propria; MS, muscularis mucosa.
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fig5: In vivo iNKT cell activation by PBS57 and esophageal eosinophil analysis. Mice (BALB/c) were exposed to repeated exposure of intravenous (i.v.) or intranasal (i.n.) PBS57  as per the protocol shown in (a). After 20–24 h of the last PBS57 or vehicle challenge, mice were killed, and eosinophil levels were evaluated in the esophagus (b) and BALF (c). Representative anti-MBP antibody-immunostained high-resolution photomicrographs of intraepithelial eosinophils in the esophagus after vehicle (d, original magnification × 100) or intranasal PBS57 challenge (e, original magnification × 100 and f, original magnification × 400). The absolute numbers of eosinophils in the esophagus of CD1d- mice and wild-type mice after intranasal PBS57 challenge of mice (g). Data are expressed as mean±s.d., n=12 mice/group. EP, epithelium; LP, lamina propria; MS, muscularis mucosa.

Mentions: We next tested whether iNKT cell activation is sufficient to induce EE in mice. Accordingly, we delivered iNKT cell-specific agonist αGalCer analog PBS5743 to naive mice as per the protocol shown (Figure 5a). An intense eosinophilia was detected in the esophagus along with moderate eosinophilia in the lung of mice given intranasal and intravenous PBS57 (Figures 5b and c). The intranasal PBS 57-challenged mice accumulated intraepithelial eosinophils in the esophageal epithelium (Figures 5d and e). The mice given intranasal or intravenous vehicle control did not have detectable levels of eosinophils in the esophageal mucosa (Figure 5f). To validate that in vivo PBS57 treatment is specific to iNKT cells, we treated CD1d- mice with intranasal PBS57. The PBS57-treated CD1d- mice did not induce EoE (Figure 5g).


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)

In vivo iNKT cell activation by PBS57 and esophageal eosinophil analysis. Mice (BALB/c) were exposed to repeated exposure of intravenous (i.v.) or intranasal (i.n.) PBS57  as per the protocol shown in (a). After 20–24 h of the last PBS57 or vehicle challenge, mice were killed, and eosinophil levels were evaluated in the esophagus (b) and BALF (c). Representative anti-MBP antibody-immunostained high-resolution photomicrographs of intraepithelial eosinophils in the esophagus after vehicle (d, original magnification × 100) or intranasal PBS57 challenge (e, original magnification × 100 and f, original magnification × 400). The absolute numbers of eosinophils in the esophagus of CD1d- mice and wild-type mice after intranasal PBS57 challenge of mice (g). Data are expressed as mean±s.d., n=12 mice/group. EP, epithelium; LP, lamina propria; MS, muscularis mucosa.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: In vivo iNKT cell activation by PBS57 and esophageal eosinophil analysis. Mice (BALB/c) were exposed to repeated exposure of intravenous (i.v.) or intranasal (i.n.) PBS57  as per the protocol shown in (a). After 20–24 h of the last PBS57 or vehicle challenge, mice were killed, and eosinophil levels were evaluated in the esophagus (b) and BALF (c). Representative anti-MBP antibody-immunostained high-resolution photomicrographs of intraepithelial eosinophils in the esophagus after vehicle (d, original magnification × 100) or intranasal PBS57 challenge (e, original magnification × 100 and f, original magnification × 400). The absolute numbers of eosinophils in the esophagus of CD1d- mice and wild-type mice after intranasal PBS57 challenge of mice (g). Data are expressed as mean±s.d., n=12 mice/group. EP, epithelium; LP, lamina propria; MS, muscularis mucosa.
Mentions: We next tested whether iNKT cell activation is sufficient to induce EE in mice. Accordingly, we delivered iNKT cell-specific agonist αGalCer analog PBS5743 to naive mice as per the protocol shown (Figure 5a). An intense eosinophilia was detected in the esophagus along with moderate eosinophilia in the lung of mice given intranasal and intravenous PBS57 (Figures 5b and c). The intranasal PBS 57-challenged mice accumulated intraepithelial eosinophils in the esophageal epithelium (Figures 5d and e). The mice given intranasal or intravenous vehicle control did not have detectable levels of eosinophils in the esophageal mucosa (Figure 5f). To validate that in vivo PBS57 treatment is specific to iNKT cells, we treated CD1d- mice with intranasal PBS57. The PBS57-treated CD1d- mice did not induce EoE (Figure 5g).

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