Department of Laboratory Medicine-Laboratory Medical Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
Department of Dermatology, Radboudumc, Nijmegen, The Netherlands.
J Transl Med. 2021 Jan 6;19(1):11. doi: 10.1186/s12967-020-02615-2.
Inflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2'deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.
炎症性疾病，如糖尿病、系统性红斑狼疮、炎症性肺病、类风湿性关节炎和多发性硬化症，但也包括移植器官的排斥和移植物抗宿主病，构成了主要的疾病负担。目前用于治疗这些疾病的免疫抑制药物类别并非总是能够治愈，且副作用较为常见。因此，需要具有改进和更具针对性作用模式的新药。潜在的候选药物是 DNA 甲基转移酶抑制剂 5-氮杂胞苷（Aza）及其衍生物 5-氮杂 2'-脱氧胞苷（DAC）。Aza 和 DAC 已在多项临床前体内研究中进行了测试。为了全面了解 Aza 和/或 DAC 可能成为潜在治疗方法的疾病，并找出信息不足的地方，我们系统地回顾了评估 Aza 或 DAC 作为治疗不同炎症性疾病的潜在疗法的临床前动物研究。此外，我们还系统地评估了研究质量和偏倚风险。在确定的 35 项研究中，我们表明，Aza 和 DAC 不仅似乎能够缓解许多炎症性疾病，而且还可以预防体内临床前动物模型中的实体器官排斥和移植物抗宿主病。Aza/DAC 已知可在体外上调 FOXP3，FOXP3 是 Treg 的主转录因子。有 17 项研究描述了其对 Treg 的影响，其中 16 项研究显示 Treg 增加。因此，增加 Treg 似乎是 Aza/DAC 预防炎症性疾病的共同机制。然而，我们还发现，许多重要的方法学细节报告得很差，导致偏倚风险不明确。因此，报告的影响可能是对真实影响的高估。
