为了研究自然杀伤细胞（NK细胞）从静脉、腹腔或肿瘤内注射引起的小鼠人体胰腺腺癌（PaC）皮下移植模型中的可能急性毒性和病理变化。在给予实验之前，用BXPC-3细胞在100只NPG携带肿瘤的小鼠（50只/性别）的皮下移植模型中植入人体PaC细胞，移植后9天进行实验。将小鼠随机分为10组，每组包括5只雄性和5只雌性。第1组小鼠以氯化钠溶液静脉给药作为溶剂对照，第2-4组小鼠以2 × 107、1 × 108和5 × 108个细胞/千克的剂量静脉注射人体外周血源性NK细胞；第5-7组小鼠以2 × 107、1 × 108和5 × 108个细胞/千克的剂量腹腔注射NK细胞；第8-10组小鼠以4 × 103、2 × 104和1 × 105个细胞/mm3的剂量肿瘤内注射NK细胞。每组只给一次剂量，对小鼠进行临床观察，并测量体重、食物摄入量、血液生化学指标和肿瘤体积。在第15天，处死小鼠进行解剖学观察和组织病理学检查。计划处死时，在第2-4组中未发现与细胞注射相关的明显或显微病理变化；在第5-7组中，雄雌性别的小鼠的脾脏髓外造血减少，以及在5 × 108个细胞/千克剂量下，雄雌性别的小鼠脾脏白髓细胞成分增加。在第8-10组中，在4 × 103和1 × 105个细胞/mm3剂量下，雄雌性别的小鼠以及在2 × 104个细胞/mm3剂量下的雌性小鼠的脾脏髓外造血减少，并且在4 × 103个细胞/mm3剂量下的雌性小鼠和在≥ 2 × 104个细胞/mm3剂量下的雄雌性别的小鼠的脾脏白髓细胞成分增加；在≥ 2 × 104个细胞/mm3剂量下的雄雌性别的小鼠中观察到肺部和支气管周围血管/支气管炎症细胞浸润，以及在1 × 105个细胞/mm3剂量下的雄雌性别的小鼠中观察到肝脏炎症细胞浸润。在每组中，未观察到临床观察、体重、食物摄入或血液生化学方面具有毒理学意义的其他异常变化。在我们的研究中，静脉注射似乎是给予NK细胞给予人体PaC携带的小鼠的最安全方法。尽管大多数病理变化都较轻，但通过腹膜或肿瘤内给药方式影响最多的器官是脾脏、肝脏和肺脏。Copyright © 2023 Elsevier B.V. All rights reserved.

To investigate the possible acute toxicities and pathological changes associated with intravenous, intraperitoneal, or intratumoral injection of natural killer (NK) cells in mice subcutaneously bearing human pancreatic adenocarcinoma (PaC).100 NPG tumor-bearing mice (50/sex) were engrafted subcutaneously with human PaC BXPC-3 cells 9 days before administration. They were randomly divided into 10 groups with 5 males and 5 females in each group. Mice in Group 1 were given sodium chloride intravenously as vehicle control, and mice in Groups 2-4 human peripheral blood-derived NK cells intravenously at doses of 2 × 107, 1 × 108, and 5 × 108 cells/kg, respectively; mice in Groups 5-7 were injected with NK cells intraperitoneally at doses of 2 × 107, 1 × 108, and 5 × 108 cells/kg, respectively, and mice in Groups 8-10 with NK cells intratumorally at doses of 4 × 103, 2 × 104, and 1 × 105 cells/mm3, respectively. Each group was given a single dose; the mice were observed clinically, and body weight, food intake, blood biochemistry, and tumor volume were measured. On Day 15, the mice were euthanized for gross anatomy and histopathology.On planned euthanasia, in Groups 2-4 no gross or microscopic pathological changes related to cells injection were found; in Groups 5-7 mice of both sexes showed a decrease in extramedullary hematopoiesis of spleen, and at the dose of 5 × 108 cells/kg, mice of both sexes showed an increase in the composition of spleen white pulp cells. In Groups 8-10, mice of both sexes at doses of 4 × 103 and 1 × 105 cells/mm3 and female mice at the dose of 2 × 104 cells/mm3 showed a decrease in extramedullary hematopoiesis of spleen, and female mice at a dose of 4 × 103 cells/mm3 and mice of both sexes at doses of ≥ 2 × 104 cells/mm3 showed an increase in the composition of spleen white pulp cells; perivascular/peribronchiolar inflammatory cell infiltration in lung and bronchus was observed in mice of both sexes at doses of ≥ 2 × 104 cells/mm3, and inflammatory cell infiltration in liver was observed in mice of both sexes at a dose of 1 × 105 cells/mm3. No other abnormal changes with toxicological significance in clinical observation, body weight, food intake, or blood biochemistry were observed in each group.In our study intravenous injection appears the safest way to give NK cells to human PaC-bearing mice. Using intraperitoneal or intratumoral administration, spleen, liver, and lung were the most often affected organs, albeit with mostly mild pathological changes.Copyright © 2023 Elsevier B.V. All rights reserved.