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*
Department of Medical Microbiology and Immunology, University of Göteborg, Göteborg, Sweden;
Department of Molecular Biology, Astra Hässle AB, Molndal, Sweden; and
Department of Immunology, The Wenner-Gren Institute, Arrhenius Laboratories for Natural Sciences, Stockholm University, Stockholm, Sweden
We recently developed a novel immunomodulating gene fusion protein,
CTA1-DD, that combines the ADP-ribosylating ability of cholera toxin
(CT) with a dimer of an Ig-binding fragment, D, of
Staphylococcus aureus protein A. The CTA1-DD adjuvant
was found to be nontoxic and greatly augmented T cell-dependent
responses to soluble protein Ags after systemic as well as mucosal
immunizations. Here we show that CTA1-DD does not appear to form immune
complexes or bind to soluble Ig following injections, but, rather, it
binds directly to B cells of all isotypes, including naive
IgD+ cells. No binding was observed to macrophages or
dendritic cells. Immunizations in Fc
R (common FcR
-chain)- and
FcRII-deficient mice demonstrated that CTA1-DD exerted unaltered
enhancing effects, indicating that FcR-expressing cells are not
required for the adjuvant function. Whereas CT failed to augment Ab
responses to high m.w. dextran B512 in athymic mice, CTA1-DD was highly
efficient, demonstrating that T cell-independent responses were also
enhanced by this adjuvant. In normal mice both CT and CTA1-DD, but not
the enzymatically inactive CTA1-R7K-DD mutant, were efficient enhancers
of T cell-dependent as well as T cell-independent responses, and both
promoted germinal center formation following immunizations. Although CT
augmented apoptosis in Ag receptor-activated B cells, CTA1-DD strongly
counteracted apoptosis by inducing Bcl-2 in a dose-dependent manner, a
mechanism that was independent of the CD19 coreceptor. However, in the
presence of CD40 stimulation, apoptosis was low and unaffected by CT,
suggesting that the adjuvant effect of CT is dependent on the presence
of activated CD40 ligand-expressing T cells.
This article has been cited by other articles:
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  S. Arce, H. F. Nawar, G. Muehlinghaus, M. W. Russell, and T. D. Connell In Vitro Induction of Immunoglobulin A (IgA)- and IgM-Secreting Plasma Blasts by Cholera Toxin Depends on T-Cell Help and Is Mediated by CD154 Up-Regulation and Inhibition of Gamma Interferon Synthesis Infect. Immun., March 1, 2007; 75(3): 1413 - 1423. [Abstract] [Full Text] [PDF]
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C. S. Andersen, J. Dietrich, E. M. Agger, N. Y. Lycke, K. Lovgren, and P. Andersen The Combined CTA1-DD/ISCOMs Vector Is an Effective Intranasal Adjuvant for Boosting Prior Mycobacterium bovis BCG Immunity to Mycobacterium tuberculosis Infect. Immun., January 1, 2007; 75(1): 408 - 416. [Abstract] [Full Text] [PDF]
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 A. Helgeby, N. C. Robson, A. M. Donachie, H. Beackock-Sharp, K. Lovgren, K. Schon, A. Mowat, and N. Y. Lycke The Combined CTA1-DD/ISCOM Adjuvant Vector Promotes Priming of Mucosal and Systemic Immunity to Incorporated Antigens by Specific Targeting of B Cells J. Immunol., March 15, 2006; 176(6): 3697 - 3706. [Abstract] [Full Text] [PDF]
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A. Duverger, R. J. Jackson, F. W. van Ginkel, R. Fischer, A. Tafaro, S. H. Leppla, K. Fujihashi, H. Kiyono, J. R. McGhee, and P. N. Boyaka Bacillus anthracis Edema Toxin Acts as an Adjuvant for Mucosal Immune Responses to Nasally Administered Vaccine Antigens J. Immunol., February 1, 2006; 176(3): 1776 - 1783. [Abstract] [Full Text] [PDF]
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D. Grdic, L. Ekman, K. Schon, K. Lindgren, J. Mattsson, K.-E. Magnusson, P. Ricciardi-Castagnoli, and N. Lycke Splenic Marginal Zone Dendritic Cells Mediate the Cholera Toxin Adjuvant Effect: Dependence on the ADP-Ribosyltransferase Activity of the Holotoxin J. Immunol., October 15, 2005; 175(8): 5192 - 5202. [Abstract] [Full Text] [PDF]
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A. M. Eriksson, K. M. Schon, and N. Y. Lycke The Cholera Toxin-Derived CTA1-DD Vaccine Adjuvant Administered Intranasally Does Not Cause Inflammation or Accumulate in the Nervous Tissues J. Immunol., September 1, 2004; 173(5): 3310 - 3319. [Abstract] [Full Text] [PDF]
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K. C. Bagley, S. F. Abdelwahab, R. G. Tuskan, and G. K. Lewis An Enzymatically Active A Domain Is Required for Cholera-Like Enterotoxins To Induce a Long-Lived Blockade on the Induction of Oral Tolerance: New Method for Screening Mucosal Adjuvants Infect. Immun., December 1, 2003; 71(12): 6850 - 6856. [Abstract] [Full Text] [PDF]
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E. Gardby, J. Wrammert, K. Schon, L. Ekman, T. Leanderson, and N. Lycke Strong Differential Regulation of Serum and Mucosal IgA Responses as Revealed in CD28-Deficient Mice Using Cholera Toxin Adjuvant J. Immunol., January 1, 2003; 170(1): 55 - 63. [Abstract] [Full Text] [PDF]
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