1. Academic Validation
  2. Altered keratin 17 peptide ligands inhibit in vitro proliferation of keratinocytes and T cells isolated from patients with psoriasis

Altered keratin 17 peptide ligands inhibit in vitro proliferation of keratinocytes and T cells isolated from patients with psoriasis

  • J Am Acad Dermatol. 2006 Jun;54(6):992-1002. doi: 10.1016/j.jaad.2006.02.033.
Zhu Shen 1 Ling Chen Yu-F Liu Tian-W Gao Gang Wang Xue-L Fan Jian-Y Fan Ping-S Fan Chun-Y Li Bin Liu Yu-P Dang Cheng-X Li
Affiliations

Affiliation

  • 1 Department of Dermatology, XiJing Hospital, Fourth Military Medical University, Xi'an, China. shenzhu@fmmu.edu.cn
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-DRB1*07-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-beta. 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 microg.mL(-1) and 100 microg.mL(-1) with 119R, 100 microg.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.

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