Methotrexate and BAFF interaction prevents immunization against TNF inhibitors
Methotrexate and BAFF interaction prevents immunization against TNF inhibitors
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DOI：
10.1136/annrheumdis-2018-213403
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发表时间：
2018-10-01
影响因子：
27.4
通讯作者：
Mariette, Xavier
中科院分区：
文献类型：
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作者：
Bitoun, Samuel;Nocturne, Gaetane;Mariette, Xavier
目的肿瘤坏死因子抑制物(TNFi)可诱导自身免疫性疾病(AID)患者产生抗药物抗体(ADA)，导致临床耐药。我们探索了一种使用甲氨蝶呤(MTX)来降低这种免疫风险的新方法。方法对生物药物免疫力较高的AID模型BAFF转基因小鼠(BAFFtg)进行不同的TNFi处理。我们调查了在第一次接触TNFi期间单疗程MTX的效果。比较了野生型(WT)和BAFFtg小鼠在涉及MTX相关的嘌呤能代谢、腺苷产生和调节性B细胞(Bregs)的B细胞表面标志物。我们将这项研究转化为ABIRISK队列中的猕猴和类风湿性关节炎患者，以确定血清BAFF水平和MTX之间是否存在相互作用，从而阻止免疫。结果在BAFFtg中，但在WT小鼠或猕猴中，单疗程MTX阻止了针对TNFi的免疫并保持了超过52周的药物浓度。与WT小鼠相比，BAFFtg小鼠B细胞表达更多的CD73和CD39。MTX可诱导B细胞释放腺苷，并增加Bregs和前体细胞的数量。使用CD73封闭抗体可逆转MTX诱导的耐受。在ABIRISK队列中接受TNFi治疗的慢性炎症性疾病患者中，高BAFF水平仅在接受MTX联合治疗的患者中与ADA对TNFi的缺失相关。结论MTX和BAFF在小鼠体内存在相互作用，CD73、腺苷和调节性B细胞是这种现象的关键因素。MTX和BAFF在患者体内也相互作用，以防止ADA的形成。
Objectives TNF inhibitors (TNFi) can induce anti-drug antibodies (ADA) in patients with autoimmune diseases (AID) leading to clinical resistance. We explored a new way of using methotrexate (MTX) to decrease this risk of immunisation.Methods We treated BAFF transgenic (BAFFtg) mice, a model of AID in which immunisation against biologic drugs is high, with different TNFi. We investigated the effect of a single course of MTX during the first exposure to TNFi. Wild-type (WT) and BAFFtg mice were compared for B-Cell surface markers involved in MTX-related purinergic metabolism, adenosine production and regulatory B-cells (Bregs). We translated the study to macaques and patients with rheumatoid arthritis from the ABIRISK cohort to determine if there was an interaction between serum BAFF levels and MTX that prevented immuniation.Results In BAFFtg but not in WT mice or macaques, a single course of MTX prevented immunisation against TNFi and maintained drug concentration for over 52 weeks. BAFFtg mice B-cells expressed more CD73 and CD39 compared to WT mice. MTX induced adenosine release from B cells and increased Bregs and precursors. Use of CD73 blocking antibodies reversed MTX-induced tolerance. In patients from the ABIRISK cohort treated with TNFi for chronic inflammatory diseases, high BAFF serum level correlated with absence of ADA to TNFi only in patients cotreated with MTX but not in patients on TNFi monotherapy.Conclusion MTX and BAFF interact in mice where CD73, adenosine and regulatory B cells were identified as key actors in this phenomenon. MTX and BAFF also interact in patients to prevent ADA formation.