Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, China.
Department of Clinical Laboratory, PLA Rocket Characteristic Medical Center, Beijing, China.
Int J Radiat Oncol Biol Phys. 2020 Dec 1;108(5):1357-1367. doi: 10.1016/j.ijrobp.2020.07.2325. Epub 2020 Aug 3.
Recombinant human thrombopoietin (rhTPO) has been evaluated as a therapeutic intervention for radiation-induced myelosuppression. However, the immunogenicity induced by a repeated-dosing strategy raises concerns about the therapeutic use of rhTPO. In this study, single-dose administration of rhTPO was evaluated for efficacy in the hematopoietic response and survival effect on mice and nonhuman primates exposed to total body irradiation (TBI).
Survival of lethally (9.0 Gy) irradiated C57BL/6J male mice was observed for 30 days after irradiation. Hematologic evaluations were performed on C57BL/6J male mice given a sublethal dose of radiation (6.5 Gy). Furthermore, in sublethally irradiated mice, we performed bone marrow (BM) histologic evaluation and evaluated BM-derived clonogenic activity. Next, the proportion and number of hematopoietic stem cells (HSCs) were analyzed. Competitive repopulation experiments were conducted to assess the multilineage engraftment of irradiated HSCs after BM transplantation. Flow cytometry was used to evaluate DNA damage, cell apoptosis, and cell cycle stage in HSCs after irradiation. Finally, we evaluated the efficacy of a single dose of rhTPO administered after 7 Gy TBI in male and female rhesus monkeys.
A single administration of rhTPO 2 hours after irradiation significantly mitigated TBI-induced death in mice. rhTPO promoted multilineage hematopoietic recovery, increasing peripheral blood cell counts, BM cellularity, and BM colony-forming ability. rhTPO administration led to an accelerated recovery of BM HSC frequency and multilineage engraftment after transplantation. rhTPO treatment reduced radiation-induced DNA damage and apoptosis and promoted HSC proliferation after TBI. Notably, a single administration of rhTPO significantly promoted multilineage hematopoietic recovery and improved survival in nonhuman primates after TBI.
These findings indicate that early intervention with a single administration of rhTPO may represent a promising and effective radiomitigative strategy for victims of radiation disasters.
重组人血小板生成素（rhTPO）已被评估为治疗辐射引起的骨髓抑制的一种治疗干预手段。然而，重复给药策略引起的免疫原性引起了对 rhTPO 治疗用途的关注。在这项研究中，评估了 rhTPO 的单次给药在接受全身照射（TBI）的小鼠和非人类灵长类动物中的造血反应和生存效果。
观察致死性（9.0 Gy）照射后 C57BL/6J 雄性小鼠的 30 天存活率。对接受亚致死剂量辐射（6.5 Gy）的 C57BL/6J 雄性小鼠进行血液学评估。此外，在亚致死性照射的小鼠中，我们进行了骨髓（BM）组织学评估，并评估了 BM 源性集落形成活性。接下来，分析造血干细胞（HSCs）的比例和数量。进行竞争再植入实验，以评估 BM 移植后照射 HSCs 的多谱系植入。流式细胞术用于评估照射后 HSCs 中的 DNA 损伤、细胞凋亡和细胞周期阶段。最后，我们评估了在雄性和雌性恒河猴接受 7 Gy TBI 后单次给予 rhTPO 的疗效。
照射后 2 小时单次给予 rhTPO 可显著减轻 TBI 引起的小鼠死亡。rhTPO 促进多谱系造血恢复，增加外周血细胞计数、BM 细胞数和 BM 集落形成能力。rhTPO 给药导致移植后 BM HSC 频率和多谱系植入的加速恢复。rhTPO 治疗可减少辐射引起的 DNA 损伤和凋亡，并促进 TBI 后 HSC 增殖。值得注意的是，单次给予 rhTPO 可显著促进多谱系造血恢复并改善 TBI 后非人类灵长类动物的生存。
这些发现表明，早期干预单次给予 rhTPO 可能代表一种有前途和有效的辐射减毒策略，可用于辐射灾难的受害者。
