The Mucosal Vaccine Adjuvant LT(R192G/L211A) or dmLT

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Abstract

ABSTRACT

Perhaps the best-studied mucosal adjuvants are the bacterially derived ADP-ribosylating enterotoxins. This adjuvant family includes heat-labile enterotoxin of Escherichia coli (LT), cholera toxin (CT), and mutants or subunits of LT and CT. These proteins promote a multifaceted antigen-specific response, including inflammatory Th1, Th2, Th17, cytotoxic T lymphocytes (CTLs), and antibodies. However, more uniquely among adjuvant classes, they induce antigen-specific IgA antibodies and long-lasting memory to coadministered antigens when delivered mucosally or even parenterally. The purpose of this minireview is to describe the general properties, history and creation, preclinical studies, clinical studies, mechanisms of action, and considerations for use of the most promising enterotoxin-based adjuvant to date, LT(R192G/L211A) or dmLT. This review is timely due to completed, ongoing, and planned clinical investigations of dmLT in multiple vaccine formulations by government, nonprofit, and industry groups in the United States and abroad.

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Most cited references 89

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Marc Veldhoen (2017)

Although interleukin 17 (IL-17) has modest activity on its own, it has a substantial impact in immunity through its synergistic action with other factors and its self-sustaining feedback loop. Veldhoen discusses the role of IL-17 during infections.

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Harvey Cantor, Thomas Korn, Estelle Bettelli … (2010)

T helper type 17 (TH17) cells are highly proinflammatory effector T cells that are characterized by the production of high amounts of IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 cells have been associated with a number of autoimmune diseases. However, it is not clear whether TH17 cells can also serve as effective helper cells. Here we show that TH17 cells can function as B-cell helpers in that they not only induce a strong proliferative response of B cells in vitro but also trigger antibody production with class switch recombination in vivo. Transfer of TH17 cells into WT or T-cell receptor alpha-deficient mice, which lack endogenous T cells, induces a pronounced antibody response with preferential isotype class switching to IgG1, IgG2a, IgG2b, and IgG3, as well as the formation of germinal centers. Conversely, blockade of IL-17 signaling results in a significant reduction in both number and size of germinal centers. Whereas IL-21 is known to help B cells, IL-17 on its own drives B cells to undergo preferential isotype class switching to IgG2a and IgG3 subtypes. These observations provide insights into the unappreciated role of TH17 cells and their signature cytokines in mediating B-cell differentiation and class switch recombination.

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Author and article information

Contributors

Christopher J. Papasian: Role: Editor

Journal

Journal ID (nlm-ta): mSphere

Journal ID (iso-abbrev): mSphere

Journal ID (hwp): msph

Journal ID (pmc): msph

Journal ID (publisher-id): mSphere

Title: mSphere

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Electronic): 2379-5042

Publication date (Electronic): 25 July 2018

Publication date Collection: Jul-Aug 2018

Volume: 3

Issue: 4

Electronic Location Identifier: e00215-18

Affiliations

[a ]Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA

UMKC School of Medicine

Author notes

Address correspondence to Elizabeth B. Norton, enorton@ 123456tulane.edu .

Citation Clements JD, Norton EB. 2018. The mucosal vaccine adjuvant LT(R192G/L211A) or dmLT. mSphere 3:e00215-18. https://doi.org/10.1128/mSphere.00215-18.

Article

Publisher ID: mSphere00215-18

DOI: 10.1128/mSphere.00215-18

PMC ID: 6060342

PubMed ID: 30045966

SO-VID: e678ddc5-49ba-4457-ad7a-b176bb933b70

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Page count

Figures: 2, Tables: 2, Equations: 0, References: 94, Pages: 17, Words: 10617

Funding

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;

Award ID: R01AI114697

Award Recipient : Elizabeth B. Norton

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID), https://doi.org/10.13039/100000060;

Award ID: NIH2012146

Award Recipient : John D. Clements Award Recipient : Elizabeth B. Norton

Custom metadata

cover-date July/August 2018

Keywords: adjuvant,dmlt,mucosal vaccines

Data availability:

Keywords: adjuvant, dmlt, mucosal vaccines

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