Tsuji Naoko, Agbor-Enoh Sean
Renal Diagnostics and Therapeutics Unit, National Institutes of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland.
Lasker Clinical Research Tenure Track Investigator and Laboratory Chief, Laboratory of Applied Precision Omics, National Heart, Lung, and Blood Institute, Bethesda, Maryland; Lung Transplantation Program, Johns Hopkins School of Medicine, Baltimore, M.
J Heart Lung Transplant. 2021 Jun;40(6):405-413. doi: 10.1016/j.healun.2021.03.007. Epub 2021 Mar 24.
Cell-free DNA, measured as donor-derived cell-free DNA is developed as a non-specific biomarker for allograft injury and transplant rejection. However, cell-free DNA characteristics are more specific, its fragment length, nucleotide content, and composition, as well as the tissue source of origin, are intrinsically linked to the underlying disease pathogenesis, showing distinct features in acute cellular rejection and antibody-mediated rejection for example. Further, cell-free DNA and cell-free mitochondrial DNA can directly trigger tissue injury as damage-associated molecular patterns through three major intracellular receptors, toll-like receptor 9 , cyclic guanosine monophosphate-adenosine monophosphate synthase, and inflammasomes (i.e., absent in melanoma 2: AIM2). Therefore, in addition to its role as a non-specific marker for allograft injury, cell-free DNA analysis may be used to phenotype transplant rejection, and to non-invasively point the underlying molecular mechanisms with allograft injury. Novel treatment approaches targeting these cell-free DNA pathways may be useful to treat transplant rejection and prevent end-organ dysfunction. In this review, we discuss the link between cell-free DNA characteristics and disease, the role of cell-free DNA as a damage-associated molecular pattern, and novel therapeutics targeting these cell-free DNA molecular pathways and their potential utility to treat transplant rejection.
以供体来源的游离DNA来衡量的游离DNA，已被开发为同种异体移植损伤和移植排斥反应的非特异性生物标志物。然而，游离DNA的特征更具特异性，其片段长度、核苷酸含量和组成，以及起源的组织来源，都与潜在的疾病发病机制内在相关，例如在急性细胞排斥反应和抗体介导的排斥反应中表现出明显特征。此外，游离DNA和游离线粒体DNA可通过三种主要的细胞内受体，即Toll样受体9、环磷酸鸟苷-磷酸腺苷合酶和炎性小体（即黑色素瘤2缺失：AIM2），作为损伤相关分子模式直接触发组织损伤。因此，除了作为同种异体移植损伤的非特异性标志物的作用外，游离DNA分析还可用于对移植排斥反应进行表型分析，并以非侵入性方式指出同种异体移植损伤的潜在分子机制。针对这些游离DNA途径的新型治疗方法可能有助于治疗移植排斥反应并预防终末器官功能障碍。在本综述中，我们讨论了游离DNA特征与疾病之间的联系、游离DNA作为损伤相关分子模式的作用，以及针对这些游离DNA分子途径的新型疗法及其治疗移植排斥反应的潜在效用。
