Peptide analogues of a T-cell epitope of ricin toxin A-chain prevent agonist-mediated human T-cell response.
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.
Castelletti
D
D
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.
Colombatti
M
M
D000596:Amino Acids / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012276:Ricin / Q000031:analogs & derivatives* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D000596:Amino Acids; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D012276:Ricin