Role of CTA1R7K-COL-DD as a Novel Therapeutic Mucosal Tolerance-Inducing Vector for Treatment of Collagen-Induced Arthritis
Role of CTA1R7K-COL-DD as a Novel Therapeutic Mucosal Tolerance-Inducing Vector for Treatment of Collagen-Induced Arthritis
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DOI：
10.1002/art.24566
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发表时间：
2009-06-01
影响因子：
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通讯作者：
Lycke, Nils
中科院分区：
文献类型：
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作者：
Hasselberg, Annemarie;Schon, Karin;Lycke, Nils
Objective.为了确定当在DBA/1小鼠中鼻内给药时，携带II类主要组织相容性复合体H-2（q）-限制性II型胶原肽aa 259-274的霍乱毒素衍生的新型免疫调节融合蛋白CTA 1 R7 K-COL-DD是否可以诱导治疗耐受并预防胶原诱导的关节炎（CIA），并评估粘膜上的ADP-核糖基化是否发挥调节功能，从而可以控制耐受或免疫增强的结果。用CTA 1 R7 K-COL-DI鼻内处理患有CIA的DBA/1小鼠。发病后连续观察46天。评估疾病的临床评分、炎症和骨质侵蚀的组织学检查，并测定血清或回忆抗原刺激的脾细胞上清液中的细胞因子水平。CTA 1 R7 K-COL-DD的保护作用导致大约60%的小鼠在治疗后没有疾病的临床体征或组织学证据，而那些患有CIA的小鼠的疾病明显较轻，骨侵蚀较少。保护性状态与血清中抗胶原抗体IgG 1、IgG 2a、IgG 2b和IgG 3滴度的降低以及白细胞介素-6（IL-6）、IL-17和干扰素-γ产生的显著减少相关，而血清和T细胞水平的IL-10水平均显著上调。酶失活突变体融合蛋白CTA 1 R7 K-COL-DD提供了实质性的治疗保护，对CIA鼻内给药后。该效应背后的机制似乎是由粘膜暴露于含有CTA 1 R7 K-COL-DD载体的肽诱导的肽特异性调节性T细胞介导的。此外，粘膜上的ADP-核糖基化作为控制粘膜耐受性或免疫性的关键调节剂。
Objective. To determine whether a cholera toxin-derived, novel immunomodulating fusion protein, CTA1R7K-COL-DD, carrying the class II major histocompatibility complex H-2(q)-restricted type II collagen peptide aa 259-274, can induce therapeutic tolerance and prevent collagen-induced arthritis (CIA) when administered intranasally in DBA/1 mice, and to assess whether ADP-ribosylation at the mucosal membranes exerts a regulatory function such that the outcome of tolerance or immune enhancement can be controlled.Methods. DBA/1 mice with CIA were treated intranasally with CTA1R7K-COL-DI). The therapeutic effect was monitored for 46 days after the onset of disease. Clinical scoring of disease, histologic examination of inflammation, and bone erosion were assessed, and cytokine levels were determined in the serum or supernatants from splenocytes stimulated with recall antigen.Results. The protective effect of CTA1R7K-COL-DD resulted in roughly 60% of the mice having no clinical signs or histologic evidence of disease after treatment, and those with CIA had significantly milder disease with less bone erosion. The protective status was associated with lower serum titers of IgG1, IgG2a, IgG2b, and IgG3 anticollagen and a substantial decrease in the production of interleukin-6 (IL-6), IL-17, and interferon-gamma, while levels of IL-10 were markedly up-regulated both in the serum and at the T cell level.Conclusion. The enzymatically inactive mutant fusion protein CTA1R7K-COL-DD provided substantial therapeutic protection against CIA following intranasal administration. The mechanism behind the effect appears to be mediated by peptide-specific regulatory T cells induced by mucosal exposure to the peptide containing CTA1R7K-COL-DD vector. In addition, ADP-ribosylation at the mucosal membranes acts as a key regulator controlling mucosal tolerance or immunity.