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Altered keratin 17 peptide ligands inhibit in vitro proliferation of keratinocytes and T cells isolated from patients with psoriasis - 09/08/11

Doi : 10.1016/j.jaad.2006.02.033 
Zhu Shen, MD, PhD a, , Ling Chen, MD a, Yu-F. Liu, MD a, Tian-W. Gao, MD, PhD a, Gang Wang, MD, PhD a, Xue-L. Fan, MD, PhD a, Jian-Y. Fan, MD b, Ping-S. Fan, MD, PhD a, Chun-Y. Li, MD, PhD a, Bin Liu, MD a, Yu-P. Dang, MD a, Cheng-X. Li, MD, PhD a
a From the Departments of Dermatology, XiJing Hospital, Fourth Military Medical University, Xi’an 
b Guangzhou General Hospital of Guangzhou Military Command, Guangzhou 

Correspondence to: Zhu Shen, MD, PhD, Department of Dermatology, Center of Dermatology of Chinese PLA, National Key Discipline, XiJing Hospital, Fourth Military Medical University, Xi’an 710032, China.

Xi’an, China

Abstract

Background

Identification of critical autoantigenic T-cell epitopes is key to developing antigen-based therapies for autoimmune diseases, including psoriasis. Our previous work demonstrated that 3 peptides on keratin 17 are able to stimulate peripheral blood lymphocytes of HLA-DRB107-positive patients with psoriasis and to serve as immunodominant T-cell epitopes.

Objective

We sought to determine antagonistic altered peptide ligands to psoriatic T cells with a down-modulatory effect in inhibiting keratinocyte proliferation.

Methods

Psoriatic altered peptide ligands were generated by single alanine residue substitutions at a critical T-cell receptor contact residue position. Antagonistic altered peptide ligands were identified by suppression screening of psoriatic T-cell activation and keratinocyte proliferation.

Results

Altered peptide ligands 119R and 355L can inhibit psoriatic T-cell activation more effectively than other altered peptide ligands, especially 355L, with inhibition of T-cell proliferation and the secretion of interferon gamma and interleukin 2 in parallel with the up-regulation of interleukins 4 and 10 as well as transforming growth factor-β. In coincubation assay, altered peptide ligands 119R and 355L can down-regulate the function of psoriatic T cells more effectively than wild-type epitopes solely, but less effectively than altered peptide ligands solely. In prepulse assay altered peptide ligand 119R can down-regulate the activation of psoriatic T cells more effectively than in coincubation but less effectively as compared with altered peptide ligand 119R only. Altered peptide ligand 355L was also shown to have a similar presentation. T-cell culture supernatants (1:100) from the concentrations (10 μg · mL−1 and 100 μg · mL−1 with 119R, 100 μg · mL−1 with 355L) were more effective than the other ratios in inhibiting keratinocyte proliferation.

Limitations

This study had a relatively small sample size (52 patients and 48 healthy controls).

Conclusion

Our findings show that the altered peptide ligands 119R (VAALEEANTELEVKI) and 355L (ENRYCVQASQIQGLI) are capable of inhibiting proliferative responses of psoriatic T cells and keratinocyte proliferation in vitro, at least, with enhanced helper T cell type 2 polarization. Thus, to our knowledge, this article is the first report of the demonstration of therapeutic activity of altered peptide ligands derived from keratin 17.

Le texte complet de cet article est disponible en PDF.

Abbreviations used : APC, GAS, GST, IFN, IL, KC-SFM, MHC, MTT


Plan


 Funding sources: Outstanding Doctor Degree Foundation of Fourth Military Medical University (2003004).
Conflicts of interest: None identified.
Presented at the Ninth International Congress of Dermatology, May 19-22, 2004, Beijing, China.
Reprints not available from the authors.


© 2006  American Academy of Dermatology, Inc.. Publié par Elsevier Masson SAS. Tous droits réservés.
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Vol 54 - N° 6

P. 992-1002 - juin 2006 Retour au numéro
Article précédent Article précédent
  • Development and reliability testing of a standardized questionnaire to assess psoriasis phenotype
  • Alison Ehrlich, Troy Koch, Bijal Amin, David J. Liewehr, Seth M. Steinberg, Maria L. Turner, Andrew Blauvelt
| Article suivant Article suivant
  • Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy
  • Trevor Markham, Ronan Mullan, Lucy Golden-Mason, Sarah Rogers, Barry Bresnihan, Oliver FitzGerald, Ursula Fearon, Douglas J. Veale

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