Vasco Maria, Benincasa Giuditta, Fiorito Carmela, Faenza Mario, De Rosa Paride, Maiello Ciro, Santangelo Michele, Vennarecci Giovanni, Napoli Claudio
U.O.C. Division of Clinical Immunology, Immunohematology, Transfusion Medicine and Transplant Immunology, University of Campania "Luigi Vanvitelli", Naples, Italy.
Department of Advanced Medical and Surgical Sciences (DAMSS), University of Campania "Luigi Vanvitelli", Naples, Italy.
Transplant Rev (Orlando). 2021 Apr;35(2):100609. doi: 10.1016/j.trre.2021.100609. Epub 2021 Feb 21.
The lack of a precise stratification algorithm for predicting patients at high risk of graft rejection challenges the current solid organ transplantation (SOT) clinical setting. In fact, the established biomarkers for transplantation outcomes are unable to accurately predict the onset time and severity of graft rejection (acute or chronic) as well as the individual response to immunosuppressive drugs. Thus, identifying novel molecular pathways underlying early immunological responses which can damage transplant integrity is needed to reach precision medicine and personalized therapy of SOT. Direct epigenetic-sensitive mechanisms, mainly DNA methylation and histone modifications, may play a relevant role for immune activation and long-term effects (e.g., activation of fibrotic processes) which may be translated in new non-invasive biomarkers and drug targets. In particular, the measure of DNA methylation by using the blood-based "epigenetic clock" system may be an added value to the donor eligibility criteria providing an estimation of the heart biological age as well as a predictive biomarkers. Besides, monitoring of DNA methylation changes may aid to predict acute vs chronic graft damage in kidney transplantation (KT) patients. For example, hypermethylation of genes belonging to the Notch and Wnt pathways showed a higher predictive value for chronic injury occurring at 12 months post-KT with respect to established clinical parameters. Detecting higher circulating cell-free DNA (cfDNA) fragments carrying hepatocyte-specific unmethylated loci in the inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), insulin like growth factor 2 receptor (IGF2R), and vitronectin (VTN) genes may be useful to predict acute graft injury after liver transplantation (LT) in serum samples. Furthermore, hypomethylation in the forkhead box P3 (FOXP3) gene may serve as a marker of infiltrating natural Treg percentage in the graft providing the ability to predict acute rejection events after heart transplantation (HTx). We aim to update on the possible clinical relevance of DNA methylation changes regulating immune-related pathways underlying acute or chronic graft rejection in KT, LT, and HTx which might be useful to prevent, monitor, and treat solid organ rejection at personalized level.
缺乏用于预测移植排斥高风险患者的精确分层算法对当前实体器官移植（SOT）临床环境构成了挑战。事实上，已确立的移植结局生物标志物无法准确预测移植排斥（急性或慢性）的发生时间和严重程度，以及个体对免疫抑制药物的反应。因此，需要识别早期免疫反应背后能够破坏移植完整性的新分子途径，以实现SOT的精准医学和个性化治疗。直接的表观遗传敏感机制，主要是DNA甲基化和组蛋白修饰，可能在免疫激活和长期效应（如纤维化过程的激活）中发挥相关作用，这些效应可能转化为新的非侵入性生物标志物和药物靶点。特别是，使用基于血液的“表观遗传时钟”系统测量DNA甲基化可能为供体资格标准增加价值，提供心脏生物学年龄的估计以及预测性生物标志物。此外，监测DNA甲基化变化可能有助于预测肾移植（KT）患者的急性与慢性移植损伤。例如，与既定临床参数相比，属于Notch和Wnt途径的基因的高甲基化对KT后12个月发生的慢性损伤具有更高的预测价值。检测携带α-胰蛋白酶抑制剂重链4（ITIH4）、胰岛素样生长因子2受体（IGF2R）和玻连蛋白（VTN）基因中肝细胞特异性未甲基化位点的循环游离DNA（cfDNA）片段增加可能有助于预测肝移植（LT）后血清样本中的急性移植损伤。此外，叉头框P3（FOXP3）基因的低甲基化可能作为移植中浸润性天然调节性T细胞百分比的标志物，具有预测心脏移植（HTx）后急性排斥事件的能力。我们旨在更新关于DNA甲基化变化在调节KT、LT和HTx中急性或慢性移植排斥潜在免疫相关途径方面的可能临床相关性，这可能有助于在个性化水平上预防、监测和治疗实体器官排斥。
