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
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改变的角蛋白 17 肽配体可抑制从银屑病患者分离的角质形成细胞和 T 细胞的体外增殖。
DOI：
10.1016/j.jaad.2006.02.033
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发表时间：
2006-06-01
影响因子：
13.8
通讯作者：
Li, Cheng-X.
中科院分区：
文献类型：
--
作者：
Shen, Zhu;Chen, Ling;Li, Cheng-X.
背景资料：关键自身抗原性T细胞表位的鉴定是开发包括银屑病在内的自身免疫性疾病的基于抗原的疗法的关键。我们以前的工作表明，角蛋白17上的3个肽能够刺激HLA-DRB1 * 07阳性银屑病患者的外周血淋巴细胞，并作为免疫显性T细胞表位。我们试图确定银屑病T细胞的拮抗性改变的肽配体，在抑制角质形成细胞proliferation.Methods的下调作用：银屑病改变的肽配体产生的单丙氨酸残基取代在一个关键的T细胞受体接触残基的位置。通过银屑病T细胞活化和角质形成细胞增殖的抑制筛选鉴定拮抗性改变的肽配体。改变的肽配体119 R和355 L可以比其他改变的肽配体，尤其是355 L，同时抑制T细胞增殖和干扰素γ和白细胞介素2的分泌，调节白细胞介素4和10以及转化生长因子β。在共孵育试验中，改变的肽配体119 R和355 L可以比单独的野生型表位更有效地下调银屑病T细胞的功能，但不如单独改变的肽配体有效。在前脉冲试验中，改变的肽配体119 R可以比在共孵育中更有效地下调银屑病T细胞的活化，但与仅改变的肽配体119 R相比效果较差。改变的肽配体355L也显示具有类似的呈递。T细胞培养物来自浓度（10 μ g. mL（-1）和100 μ g. mL（-1）与119R、100 μ g. mL（-1）与355L）的比例对角质形成细胞增殖的抑制作用优于其他比例。局限性：本研究样本量相对较小（52例患者和48例健康对照）。我们的研究结果表明，改变的肽配体119R（VAALEEANTELEVKI）和355 L（ENRYCVQASQIQGLI）能够在体外抑制银屑病T细胞的增殖反应和角质形成细胞增殖，至少，辅助性T细胞2型极化增强。因此，据我们所知，这篇文章是第一次报告的示范的治疗活性的改变肽配体来源于角蛋白17。
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 downregulate 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 mu g . mL(-1) and 100 mu g . mL(-1) with 119R, 100 mu g . 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.