Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients
Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients
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DOI：
10.1126/scitranslmed.aaa9301
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发表时间：
2015-06-03
影响因子：
17.1
通讯作者：
Thomas, Ranjeny
中科院分区：
文献类型：
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作者：
Benham, Helen;Nel, Hendrik J.;Thomas, Ranjeny
在动物体内，免疫调节性树突状细胞（DCs）暴露于自身抗原后可以以抗原特异性的方式抑制实验性关节炎。在类风湿性关节炎（RA）中，约70%的RA患者血清中存在疾病特异性抗瓜氨酸肽自身抗体（ACPA或抗CCP），并且与HLA-DRB 1风险等位基因密切相关。本研究旨在探索在一项单中心、开放标签、首次人体I期试验中，暴露于四种瓜氨酸肽抗原（命名为“Rheumavax”）的核因子κ B（NF-κ B B）抑制剂修饰的自体DC的安全性、生物学和临床效应。对18名患有瓜氨酸化肽特异性自身免疫的人类白细胞抗原（HLA）风险基因型阳性RA患者，以两个递增剂量水平皮内注射Rheumavax一次。16例RA患者作为对照。Rheumavax耐受性良好：不良事件严重程度为1级（共4级）。治疗后1个月，我们观察到效应T细胞减少，调节性T细胞与效应T细胞的比例增加;血清白细胞介素-15（IL-15）、IL-29、CX 3CL 1和CXCL 11减少;相对于对照组，T细胞对波形蛋白（447-455）-Cit 450的IL-6应答减少。Rheumavax在招募的具有最小疾病活动性的患者中未诱导疾病发作，并且在Rheumavax治疗的具有活动性疾病的患者中，DAS 28在1个月内降低。这项探索性研究证明了单次皮内注射暴露于瓜氨酸肽的自体修饰DC的安全性和生物活性，并为进一步研究评估RA中自身抗原免疫调节治疗的临床疗效和抗原特异性作用提供了依据。
In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor kappa B (NF-kappa B) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin(447-455)-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA.