Immune Tolerance Induction with Multiepitope Peptide Derived from Citrullinated Autoantigens Attenuates Arthritis Manifestations in Adjuvant Arthritis Rats
Immune Tolerance Induction with Multiepitope Peptide Derived from Citrullinated Autoantigens Attenuates Arthritis Manifestations in Adjuvant Arthritis Rats
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DOI：
10.4049/jimmunol.1402457
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发表时间：
2015-06-15
影响因子：
4.4
通讯作者：
Amital, Howard
中科院分区：
文献类型：
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作者：
Gertel, Smadar;Serre, Guy;Amital, Howard
瓜氨酸肽是类风湿性关节炎疾病特异性自身抗体的主要靶点。目前，瓜氨酸肽被用作诊断类风湿性关节炎的生物标志物，通过测定患者血清中的抗瓜氨酸蛋白Ab （ACPA）滴度。瓜氨酸化蛋白在滑膜炎症部位的积累表明它们可能是诱导耐受性的靶点。本研究的目的是确定瓜氨酸化肽是否能诱导实验性大鼠关节炎模型的耐受性。鉴于ACPA靶瓜氨酸化自身抗原的多样性，我们从主要流行的瓜氨酸化自身抗原（瓜氨酸化聚丝蛋白、纤维蛋白原、波形蛋白和II型胶原）中提取了一个多表位瓜氨酸化肽（citi - me），并研究了其对关节炎大鼠的作用。用佐剂诱导Lewis大鼠关节炎。从疾病诱导后第7天开始，大鼠隔天接受8次连续注射ctc - me。分析了临床状态和T细胞群调节的差异。在用Cit-ME治疗的佐剂性关节炎大鼠中，与未治疗的大鼠相比，疾病严重程度显著降低。此外，疾病表现的改善与调节性T细胞亚群的增加以及与Th17细胞减少相关的T细胞凋亡率的升高有关。因此，使用瓜氨酸化肽为基础的免疫疗法可能是一种很有前途的方法，用于实验性关节炎的耐受性诱导，甚至可能用于人类关节炎中acpa血清阳性的易感个体。
Citrullinated peptides are major targets of disease-specific autoantibodies in rheumatoid arthritis. Currently, citrullinated peptides are used as biomarkers for diagnosing rheumatoid arthritis by measuring anti-citrullinated protein Ab (ACPA) titers in patients' sera. The accumulation of citrullinated proteins at synovial inflammation sites suggests that they are possible targets for tolerance induction. The objective of the present study was to determine whether citrullinated peptides could induce tolerance in an experimental arthritis model in rats. In view of the multiplicity of target citrullinated autoantigens described for ACPA, we generated a multiepitope citrullinated peptide (Cit-ME), derived from major prevalent citrullinated autoantigens (citrullinated filaggrin, fibrinogen, vimentin, and collagen type II), and studied its effects on arthritic rats. Adjuvant-induced arthritis was induced in Lewis rats. Beginning at day 7 after disease induction, the rats received eight s.c. injections of Cit-ME on alternate days. Differences in clinical status and modulation of T cell populations were analyzed. In adjuvant-induced arthritis rats treated with Cit-ME, disease severity was significantly reduced compared with that of untreated rats. Moreover, amelioration of disease manifestations was related to an increased regulatory T cell subset and an elevated apoptosis rate of T cells associated with reduced Th17 cells. Thus, the use of citrullinated peptides-based immunotherapy may be a promising approach for tolerance induction in experimental arthritis and perhaps even in susceptible individuals that are ACPA-seropositive in human arthritis.