Allogeneic hematopoietic stem cell transplantation is a curative therapy for a number of hematological malignancies, but is limited by the development of graft-versus-host disease (GVHD). CD39 and CD73 form an ectoenzymatic pathway that hydrolyzes extracellular adenosine 5'-triphosphate (ATP) to adenosine, which respectively exacerbate or alleviate disease in allogeneic mouse models of GVHD. The current study aimed to explore the role of the CD39/CD73 pathway and adenosine receptor (AR) blockade in a humanized mouse model of GVHD. Immunodeficient nonobese diabetic-severe combined immunodeficiency-IL-2 receptor γnull mice were injected with human peripheral blood mononuclear cells, and subsequently injected with the CD39/CD73 antagonist αβ-methylene-ADP (APCP) (50 mg kg-1 ) or saline for 7 days, or the AR antagonist caffeine (10 mg kg-1 ) or saline for 14 days. Mice predominantly engrafted human CD4+ and CD8+ T cells, with smaller proportions of human regulatory T cells, invariant natural killer T cells, monocytes and dendritic cells. Neither APCP nor caffeine altered engraftment of these human leukocyte subsets. APCP (CD39/CD73 blockade) augmented GVHD as shown through increased weight loss and worsened liver histology, including increased leukocyte and human T-cell infiltration, and increased apoptosis. This treatment also increased serum human IL-2 concentrations and decreased the frequency of human CD39- CD73- CD4+ T cells. In contrast, caffeine (AR blockade) did not alter GVHD severity or human serum cytokine concentrations (IL-2, IL-6, IL-10 or tumor necrosis factor-α). In conclusion, blockade of CD39/CD73 but not ARs augments disease in a humanized mouse model of GVHD. These results indicate that CD39/CD73 blockade maintains sufficient extracellular ATP concentrations to promote GVHD in this model.

中文翻译：

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在人源化的移植物抗宿主病小鼠模型中，CD39 / CD73途径的药理学阻断作用但不是腺苷受体的作用会加剧疾病。

同种异体造血干细胞移植是许多血液系统恶性肿瘤的治疗方法，但受到移植物抗宿主病（GVHD）的发展的限制。CD39和CD73形成一个胞外酶途径，将胞外5'-三磷酸腺苷（ATP）水解为腺苷，这分别加重或缓解了GVHD异体小鼠模型中的疾病。当前的研究旨在探讨CD39 / CD73途径和腺苷受体（AR）阻断在人源化GVHD小鼠模型中的作用。将免疫缺陷的非肥胖型糖尿病-重度联合免疫缺陷-IL-2受体γnull小鼠注射人外周血单个核细胞，然后注射CD39 / CD73拮抗剂αβ-亚甲基-ADP（APCP）（50 mg kg-1）或生理盐水。 7天，或AR拮抗剂咖啡因（10 mg kg-1）或生理盐水治疗14天。小鼠主要植入人类CD4 +和CD8 + T细胞，而人类调节性T细胞，不变的自然杀伤性T细胞，单核细胞和树突状细胞的比例较小。APCP和咖啡因都不能改变这些人类白细胞亚群的植入。APCP（CD39 / CD73阻滞剂）通过增加体重减轻和恶化的肝脏组织学（包括白细胞和人T细胞浸润增加）和凋亡增加而增强了GVHD。该治疗还增加了血清人IL-2浓度并降低了人CD39-CD73-CD4 + T细胞的频率。相反，咖啡因（AR阻滞剂）不会改变GVHD严重程度或人血清细胞因子浓度（IL-2，IL-6，IL-10或肿瘤坏死因子-α）。结论，在人源化的GVHD小鼠模型中，对CD39 / CD73的阻断而非对AR的阻断会加剧疾病。这些结果表明，在该模型中，CD39 / CD73阻滞维持足够的细胞外ATP浓度以促进GVHD。