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By Specific Targeting of B Cells Systemic Immunity to Incorporated Antigens Vector Promotes Priming of Mucosal and the Combined

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By Specific Targeting of B Cells Systemic Immunity to Incorporated Antigens Vector Promotes Priming of Mucosal and the Combined The Combined CTA1-DD/ISCOM Adjuvant Vector Promotes Priming of Mucosal and Systemic Immunity to Incorporated Antigens by Specific Targeting of B Cells This information is current as of September 28, 2021. Anja Helgeby, Neil C. Robson, Anne M. Donachie, Helen Beackock-Sharp, Karin Lövgren, Karin Schön, Allan Mowat and Nils Y. Lycke J Immunol 2006; 176:3697-3706; ; doi: 10.4049/jimmunol.176.6.3697 Downloaded from http://www.jimmunol.org/content/176/6/3697 References This article cites 57 articles, 16 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/176/6/3697.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The Combined CTA1-DD/ISCOM Adjuvant Vector Promotes Priming of Mucosal and Systemic Immunity to Incorporated Antigens by Specific Targeting of B Cells1 Anja Helgeby,* Neil C. Robson,† Anne M. Donachie,† Helen Beackock-Sharp,† Karin Lo¨vgren,‡ Karin Scho¨n,* Allan Mowat,† and Nils Y. Lycke2* The cholera toxin A1 (CTA1)-DD/QuilA-containing, immune-stimulating complex (ISCOM) vector is a rationally designed mu- cosal adjuvant that greatly potentiates humoral and cellular immune responses. It was developed to incorporate the distinctive properties of either adjuvant alone in a combination that exerted additive enhancing effects on mucosal immune responses. In this study we demonstrate that CTA1-DD and an unrelated Ag can be incorporated together into the ISCOM, resulting in greatly augmented immunogenicity of the Ag. To demonstrate its relevance for protection against infectious diseases, we tested the vector Downloaded from incorporating PR8 Ag from the influenza virus. After intranasal immunization we found that the immunogenicity of the PR8 proteins were significantly augmented by a mechanism that was enzyme dependent, because the presence of the enzymatically inactive CTA1R7K-DD mutant largely failed to enhance the response over that seen with ISCOMs alone. The combined vector was a highly effective enhancer of a broad range of immune responses, including specific serum Abs and balanced Th1 and Th2 CD4؉ T cell priming as well as a strong mucosal IgA response. Unlike unmodified ISCOMs, Ag incorporated into the combined vector could be presented by B cells in vitro and in vivo as well as by dendritic cells; it also accumulated in B cell follicles of draining http://www.jimmunol.org/ lymph nodes when given s.c. and stimulated much enhanced germinal center reactions. Strikingly, the enhanced adjuvant activity of the combined vector was absent in B cell-deficient mice, supporting the idea that B cells are important for the adjuvant effects of the combined CTA1-DD/ISCOM vector. The Journal of Immunology, 2006, 176: 3697–3706. t has proved difficult to stimulate immune responses with Ags been limited, and vaccine-induced diarrhea is an unwanted side given at mucosal sites (1, 2). The natural response to mucosal effect when these holotoxins have been used as adjuvants in oral I Ag exposure is tolerance, and effective adjuvants are required vaccines (16). Studies have also shown that the toxins may accu- to facilitate effective priming of mucosal as well as systemic im- mulate and affect the CNS after i.n. administration (17–19). An by guest on September 28, 2021 munity after oral or intranasal (i.n)3 immunization (3–5). Few ad- increased incidence of Bell’s palsy recently caused withdrawal juvants have been found to work when given mucosally, but the from the market of an influenza vaccine containing the LT adju- effects of QuilA-containing, immune-stimulating complexes vant, which was administered i.n. (20, 21). (ISCOMs) have been well documented (6–11). Perhaps the most To circumvent the toxicity problem, we have developed an al- potent mucosal adjuvants, though, are the closely related bacterial ternative CT-based adjuvant, the CTA1-DD, a gene fusion protein enteroxins, cholera toxin (CT) and Escherichia coli heat-labile that does not bind to ganglioside receptors (22). The CTA1-DD toxin (LT) (4). These holotoxins are structurally AB5 complexes adjuvant is nontoxic in mice, but retained adjuvant function, com- that bind to most mammalian cells through ganglioside receptors parable to that of CT, when given i.n. (22, 23). It consists of the via their B subunits (12). The A1 subunit is an ADP-ribosylating enzymatically active CTA1 subunit fused in-frame with a gene enzyme that has been found to host strong adjuvant function, but encoding a dimer of the D domain from the Staphylococcus aureus is also responsible for the toxicity of the molecules (13–15). Be- protein A (24, 25), allowing it to specifically target B cells via cause of their relative toxicity, the clinical use of CT or LT has binding to their Ig receptors. In contrast, ISCOMs are taken up by dendritic cells (DCs) preferentially (22, 23, 26–30) and are more *Department of Clinical Immunology, University of Goteborg, Goteborg, Sweden; potent than CTA1-DD when given orally. Therefore, we combined †Division of Immunology, Infection, and Inflammation, University of Glasgow, Glas- CTA1-DD and ISCOMs to create one of the first rationally de- ‡ gow, Scotland; and Isconova, Uppsala, Sweden signed adjuvant vectors (31). We found that the CTA1-DD/ Received for publication August 2, 2005. Accepted for publication December ISCOM vector was highly immunogenic by the i.n. as well as the 29, 2005. oral route even with nanogram doses of Ag, inducing Ag-specific The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance serum Abs, CD4 T cell priming, and IFN-␥ production (31). with 18 U.S.C. Section 1734 solely to indicate this fact. Combinations of adjuvants have several potential advantages. In 1 This work was supported by the Swedish Research Council; the Swedish Cancer addition to targeting different APCs, they offer the possibility of Foundation, the Sahlgrenska University Hospital Foundation, European Union Grants QLK2-CT-2001-01702, QLK2-CT-1999-00228, and LSHP-CT-2003-503240, and improving the stability of pharmacologically active enzymes by the Welcome Trust. incorporating in a stable vector that can deliver them linked to Ag. 2 Address correspondence and reprint requests to Dr. Nils Lycke, Department of Micro- or nanoparticles especially have been found to be the most Clinical Immunology, University of Goteborg, 413 46 Goteborg, Sweden. E-mail effective in these adjuvant combinations and, apart from ISCOMs, address: [email protected] chitosan or virus-like particles have also been successfully tested 3 Abbreviations used in this paper: i.n, intranasal; BM, bone marrow; CLN, cervical lymph node; CT, cholera toxin; DC, dendritic cell; GC, germinal center; LT, E. coli in formulations together with mutant holotoxins or muramyl heat-labile toxin; ISCOM, QuilA-containing immune-stimulating complex. dipeptide (32, 33). Although our previous work with CTA1-DD Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 3698 COMBINED CTA1-DD/ISCOM ADJUVANT ACTS THROUGH B CELLS and p323 peptides from OVA expressed as a gene fusion protein, by electron microscopy, and the various components were analyzed for CTA1-OVA-DD, supports the idea that greatly enhanced re- comigration of protein and Quillaja saponins into fractions isolated from an sponses to CTA1-DD/ISCOM-linked Ag can be achieved, it will analytical 10–50% (w/w) sucrose gradient after centrifugation (18 h at 200,000 ϫ g, 10°C). The contents of protein and saponins in the different not be possible to create fusion proteins between CTA1 and any fractions were determined as described, using ELISA and spectrophoto- given Ag or peptide (31). Therefore, the aim of the present study metric analysis (at A214 nm), respectively. The amino acid content in each was to extend the potential of CTA1-DD/ISCOMs as an effective preparation was assessed. In some experiments we labeled the ISCOMs mucosal vaccine delivery vehicle by incorporating CTA1-DD and with CFSE. Briefly, 2 ␮l of solution, freshly prepared from a stock solution (100 mM in DMSO) of CFSE (Molecular Probes) was added per milligram the influenza virus PR8 Ag into the same ISCOM particles. In of cholesterol as the ISCOMs were prepared by mixing the lipids. Endo- addition to the ability of the novel vector to stimulate local and toxin contaminations were determined in the ISCOM preparations using systemic Ag-specific immunity, we determined to what extent the the Limulus amebocyte lysate test (LAL Endochrome; Charles River En- augmenting effects were CTA1 enzyme dependent and dissected dostestafe). The endotoxin levels were Ͻ110 endotoxin units/mg protein in the mechanisms involved in the presentation and immunogenicity all ISCOM preparations, whereas CTA1-OVA-DD, CTA1R7K-OVA-DD, and CT had endotoxin levels Ͻ 50 endotoxin units/mg protein. of the vector. Quality assessment of ISCOMs Materials and Methods We routinely analyzed the protein content in all ISCOMs using specific Animals ELISA. When sucrose-derived fractions were used, we incubated 50 ␮lof BALB/c mice (H-2d) and, when indicated, C57BL/6 (H-2b) mice were each fraction in the first row of a 96-well microtiter Maxisorp plate (Nunc) obtained from B&K Universal or Harlan Olac.
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