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Infection and Immunity, December 2003, p. 6850-6856, Vol. 71, No. 12
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.12.6850-6856.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Kenneth C. Bagley,1,2 Sayed F. Abdelwahab,1,3 Robert G. Tuskan,1 and George K. Lewis1,3*

Division of Vaccine Research, Institute of Human Virology, University of Maryland Biotechnology Institute,1 Department of Biochemistry and Molecular Biology,2 Department of Microbiology and Immunology, University of Maryland School of Medicine, University of Maryland Baltimore, Baltimore, Maryland 212013

Received 1 August 2003/ Accepted 4 September 2003

The cholera-like enterotoxins (CLETS), cholera toxin (CT) and Escherichia coli heat-labile toxin (LT), are powerful mucosal adjuvants. Here we show that these toxins also induce a long-lived blockade (of at least 6 months) on the induction of oral tolerance when they are coadministered with the antigen ovalbumin. Strikingly, only enzymatically active CLETS induced this blockade on the induction of oral tolerance. In this regard, the enzymatically inactive mutants of CT and LT, CTK63 and LTK63, and their recombinant B pentamers, rCTB and rLTB, failed to block the induction of oral tolerance, demonstrating a stringent requirement for an enzymatically active A domain in this phenomenon. Together with the results of other recent studies, these results indicate that the enzymatic activity of CLETS, most likely cyclic AMP elevation, is responsible for their adjuvant effects. The results of this study also indicate that measuring the ability of putative mucosal adjuvants to block the induction of oral tolerance may be a superior method for measuring mucosal adjuvanticity.

* Corresponding author. Mailing address: Division of Vaccine Research, Institute of Human Virology, University of Maryland Baltimore, 725 W. Lombard St., Baltimore, MD 21201. Phone: (410) 706-4688. Fax: (410) 706-4695. E-mail: lewisg{at}umbi.umd.edu.

Editor: A. D. O'Brien

Infection and Immunity, December 2003, p. 6850-6856, Vol. 71, No. 12
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.12.6850-6856.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bagley, K. C., Abdelwahab, S. F., Tuskan, R. G., Lewis, G. K. (2006). Cholera Toxin Indirectly Activates Human Monocyte-Derived Dendritic Cells In Vitro through the Production of Soluble Factors, Including Prostaglandin E2 and Nitric Oxide. CVI 13: 106-115 [Abstract] [Full Text]  
  • Hajishengallis, G., Arce, S., Gockel, C.M., Connell, T.D., Russell, M.W. (2005). Immunomodulation with Enterotoxins for the Generation of Secretory Immunity or Tolerance: Applications for Oral Infections. JDR 84: 1104-1116 [Abstract] [Full Text]  


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