M cell targeting by a Claudin 4 targeting peptide can enhance mucosal IgA responses

David D Lo,Jun Ling,A Holly Eckelhoefer

doi:10.1186/1472-6750-12-7

David D Lo, Jun Ling + Show 1 more

Open Access

https://doi.org/10.1186/1472-6750-12-7

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Abstract

BackgroundMucosal immune surveillance is thought to be largely achieved through uptake by specialized epithelial M cells. We recently identified Claudin 4 as an M cell target receptor and developed a Claudin 4 targeting peptide (CPE) that can mediate uptake of nanoparticles through Nasal Associated Lymphoid Tissue (NALT) M cells.MethodsRecombinant influenza hemagglutinin (HA) and a version with the CPE peptide at the C-terminal end was used to immunize mice by the intranasal route along with a single dose of cholera toxin as an adjuvant. Serum and mucosal IgG and IgA responses were tested for reactivity to HA.ResultsWe found that the recombinant HA was immunogenic on intranasal administration, and inclusion of the CPE targeting peptide induced higher mucosal IgA responses. This mucosal administration also induced systemic serum IgG responses with Th2 skewing, but targeting did not enhance IgG responses, suggesting that the IgG response to mucosal immunization is independent of the effects of CPE M cell targeting.ConclusionsM cell targeting mediated by a Claudin 4-specific targeting peptide can enhance mucosal IgA responses above the response to non-targeted mucosal antigen. Since Claudin 4 has also been found to be regulated in human Peyer's patch M cells, the CPE targeting peptide could be a reasonable platform delivery technology for mucosal vaccination.

Highlights

Mucosal immune surveillance is thought to be largely achieved through uptake by specialized epithelial M cells
Vaccination with Claudin targeting peptide (CPE) conjugated to HA To test the ability of CPE-mediated M cell targeting to induce mucosal immunity, we chemically conjugated the Claudin 4-targeting CPE peptide to recombinant influenza hemagglutinin (HA; extracellular domain only, truncated at the transmembrane domain - aa 1-528 [24]), and delivered this antigen intranasally along with cholera toxin in the first dose as an adjuvant
At the conjugation ratio used in this study, there were approximately ten CPE peptides conjugated per trimeric HA complex

Summary

Introduction

Mucosal immune surveillance is thought to be largely achieved through uptake by specialized epithelial M cells. Live attenuated virus vaccines such as cold-adapted influenza (e.g., FluMist®), or oral polio vaccine can provide better mucosal immunity, but these are a greater challenge to Vaccination at mucosal surfaces is a strategy that can help overcome the limitations of injected vaccines (needle disposal, trained medical staff required to administer the vaccine), and to provide the benefit of mucosal IgA responses. Progress with this strategy has been made in animal studies using two distinct approaches that could be described as bioengineering versus immunological. Antigen can be acquired by dendritic cells in the mucosal epithelium [6,7] and drain into other lymphoid tissues, so mucosal IgA responses are not always efficiently induced

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