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International Immunology Advance Access published online on February 21, 2005
International Immunology, doi:10.1093/intimm/dxh216
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received June 21, 2004
Accepted January 11, 2005

Article

Peptide analogues of a T-cell epitope of ricin toxin A-chain prevent agonist-mediated human T-cell response

D. Castelletti 1 and M. Colombatti 1*

1 Section of Immunology, Department of Pathology, University of Verona, c/o Policlinico ‘G.B. Rossi’, L.go L.A. Scuro 10, I-37134 Verona, Italy

* To whom correspondence should be addressed.
M. Colombatti, E-mail: marco.colombatti{at}univr.it


  Abstract

The clinical efficacy of immunotoxins (IT) containing ricin toxin A-chain (RTA) can be drastically reduced by anti-toxin-neutralizing antibodies developed by patients. Strategies aimed at epitope-specific modulation of the immune response must be therefore set up to broaden the clinical applicability of RTA-based IT. Prevention or reduction of humoral immune responses against RTA could be achieved by peptide-based down-modulating strategies. Peptide analogues were investigated as candidate antagonist altered peptide ligands (APL) considering the sequence of a previously identified dominant T-cell epitope of RTA (i.e. I175-E185) presented in the context of the HLA-DRB1*03011 allele. Alanine-substituted peptides provided information on the role of individual residues of the wild-type peptide and allowed to identify one antagonist APL corresponding to the double-mutant peptide E177A/A178D. The analogue E177A/A178D not only prevented the agonist from stimulating anti-RTA human T-cell clones but also failed to induce down-regulation of surface-expressed TCR, thus suggesting its possible use for in vivo immune modulation of anti-RTA responses.

Keywords: altered peptide ligands; antagonists; immune modulation; ricin toxin A-chain; T-cell epitopes.
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