Marcotte G V, Braun C M, Norman P S, Nicodemus C F, Kagey-Sobotka A, Lichtenstein L M, Essayan D M
Division of Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
J Allergy Clin Immunol. 1998 Apr;101(4 Pt 1):506-13. doi: 10.1016/S0091-6749(98)70358-6.
Peptide therapy targets T cells directly with short peptides containing multiple T-cell receptor epitopes. Murine studies suggest T-cell anergy as the mechanism of action; however, changes in T-cell cytokine profiles may be more relevant in human beings.
We sought to study the effects of peptide therapy on ex vivo antigen-specific T-cell responses.
Antigen-specific T-cell lines were generated from subjects enrolled in a double-blind, placebo controlled, two-dose study of the ALLERVAX CAT therapeutic, containing Fel d 1 peptides (ImmuLogic Pharmaceutical Corp., Waltham, Mass.) (n = 7, 8, and 7, respectively, for groups receiving placebo, 75 microg, or 750 microg). Each subject had three lines propagated before and after receiving peptide therapy; antigens used were cat hair extract, Fel d 1 peptides, and tetanus toxoid (negative control). Proliferative responses and cytokine generation from each line were assessed after two restimulations with antigen and autologous antigen-presenting cells.
The Fel d 1 peptide lines showed a dose-dependent decrease of IL-4 production (p = 0.02 and 0.025, respectively, for the 750 microg group vs both the 75 microg and placebo groups). IL-4 production from the cat hair allergen extract lines and interferon-gamma production from both the Fel d 1 peptide lines and cat hair allergen extract lines showed no statistically significant changes. The control tetanus toxoid lines showed no changes in cytokine production; there were no significant changes in proliferation with any of the antigens in any of the treatment groups. In the clinical arm of the trial, only the 750 microg dose of peptides produced a significant response.
Peptide therapy induces a significant, dose-dependent decrease in peptide-stimulated IL-4 production, consistent with either a shift in T-cell phenotype or peptide-specific T-cell tolerance.
肽疗法通过含有多个T细胞受体表位的短肽直接靶向T细胞。小鼠研究表明T细胞失能是其作用机制；然而，T细胞细胞因子谱的变化在人类中可能更具相关性。
我们试图研究肽疗法对体外抗原特异性T细胞反应的影响。
从参加ALLERVAX CAT治疗剂双盲、安慰剂对照、两剂量研究的受试者中产生抗原特异性T细胞系，该治疗剂含有猫过敏原蛋白1肽（ImmuLogic制药公司，马萨诸塞州沃尔瑟姆）（接受安慰剂、75微克或750微克的组分别为n = 7、8和7）。每个受试者在接受肽疗法前后培养三个细胞系；使用的抗原有猫毛提取物、猫过敏原蛋白1肽和破伤风类毒素（阴性对照）。在用抗原和自体抗原呈递细胞进行两次再刺激后，评估每个细胞系的增殖反应和细胞因子生成情况。
猫过敏原蛋白1肽细胞系显示IL-4产生呈剂量依赖性降低（750微克组与75微克组和安慰剂组相比，p值分别为0.02和0.025）。猫毛过敏原提取物细胞系的IL-4产生以及猫过敏原蛋白1肽细胞系和猫毛过敏原提取物细胞系的干扰素-γ产生均无统计学显著变化。对照破伤风类毒素细胞系的细胞因子产生无变化；任何治疗组中任何抗原的增殖均无显著变化。在试验的临床组中，只有750微克剂量的肽产生了显著反应。
肽疗法可诱导肽刺激的IL-4产生显著的剂量依赖性降低，这与T细胞表型转变或肽特异性T细胞耐受一致。
