Bowers Sarah M, Ng Bernard, Abdossamadi Sayeh, Kariminia Amina, Cabral David A, Cuvelier Geoffrey D E, Schultz Kirk R, Brown Kelly L
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, British Columbia Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
Transplant Cell Ther. 2023 May;29(5):303.e1-303.e9. doi: 10.1016/j.jtct.2023.02.014. Epub 2023 Feb 17.
Adenosinergic signaling has potent, context-specific effects on immune cells, particularly on the dysregulation of lymphocytes. This in turn may have a role in immune activation and loss of tolerance in such diseases as chronic graft-versus-host disease (chronic GVHD). We assessed whether changes in the enzymatic activity of adenosine deaminase 2 (ADA2), an enzyme that depletes adenosine in the extracellular space via conversion to inosine, may be associated with the onset of chronic GVHD. ADA2-specific enzyme activity was measured in plasma samples from 230 pediatric hematopoietic stem cell transplantation (HSCT) recipients enrolled on the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE)/Pediatric Blood and Marrow Transplant Consortium (PBMTC) 1202 study and compared between patients developing chronic GVHD and those not developing chronic GVHD within 12 months of transplantation. ADA2 and its relationships with 219 previously measured plasma-soluble proteins, metabolites, and immune cell populations were evaluated as well. Plasma ADA2 enzyme activity was significantly elevated in pediatric HSCT recipients at the onset of chronic GVHD compared to patients without chronic GVHD and was not associated with prior history of acute GVHD or generalized inflammation as measured by C-reactive protein concentration. ADA2-specific enzyme activity met our criteria as a potential diagnostic biomarker of chronic GVHD (effect ratio ≥1.30 or ≤.75; area under the receiver operating characteristic curve ≥.60; P < .05) and was positively associated with markers of immune activation previously identified in pediatric chronic GVHD patients. These results support the potential of ADA2 enzyme activity, in combination with other biomarkers and subject to future validation, to aid the diagnosis of chronic GVHD in children post-HSCT.
腺苷能信号传导对免疫细胞具有强大的、特定背景下的作用，尤其是对淋巴细胞的失调。这反过来可能在诸如慢性移植物抗宿主病（慢性GVHD）等疾病的免疫激活和耐受性丧失中发挥作用。我们评估了腺苷脱氨酶2（ADA2）的酶活性变化（一种通过转化为肌苷来消耗细胞外空间中腺苷的酶）是否可能与慢性GVHD的发病有关。在参与儿童癌症后期效应应用生物标志物（ABLE）/儿科血液和骨髓移植联盟（PBMTC）1202研究的230名儿科造血干细胞移植（HSCT）受者的血浆样本中测量ADA2特异性酶活性，并比较移植后12个月内发生慢性GVHD的患者和未发生慢性GVHD的患者。还评估了ADA2及其与219种先前测量的血浆可溶性蛋白、代谢物和免疫细胞群体的关系。与没有慢性GVHD的患者相比，慢性GVHD发病时儿科HSCT受者的血浆ADA2酶活性显著升高，并且与急性GVHD或通过C反应蛋白浓度测量的全身性炎症的既往病史无关。ADA2特异性酶活性符合我们作为慢性GVHD潜在诊断生物标志物的标准（效应比≥1.30或≤0.75；受试者工作特征曲线下面积≥0.60；P<0.05），并且与先前在儿科慢性GVHD患者中确定的免疫激活标志物呈正相关。这些结果支持ADA2酶活性与其他生物标志物结合并有待未来验证，以辅助HSCT后儿童慢性GVHD诊断的潜力。
