Neelis K J, Dubbelman Y D, Wognum A W, Thomas G R, Eaton D L, Egeland T, Wagemaker G
Institute of Hematology, Erasmus University Rotterdam, The Netherlands.
Exp Hematol. 1997 Sep;25(10):1094-103.
The efficacy of recombinant human thrombopoietin (TPO) and recombinant human granulocyte colony stimulating factor (G-CSF) in stimulating platelet and neutrophil recovery was evaluated in a placebo-controlled study involving transplantation of limited numbers (1-3 x 10(4)/kg) of highly purified autologous stem cells (CD34++/RhLA-DR[dull]) into rhesus monkeys after the animals were subjected to 8 Gy of total body irradiation (TBI) (x-rays). The grafts shortened profound TBI-induced pancytopenia from 5 to 6 weeks to 3 weeks. Daily subcutaneous (sc) injection of TPO (10 microg/kg/day, days 1-21 after TBI) did not stimulate platelet regeneration after transplantation either alone or in combination with G-CSF (5 microg/kg/day sc, days 1-21 after TBI). G-CSF treatment failed to prevent neutropenia in the monkeys and did not stimulate recovery to normal neutrophil levels. Simultaneous administration of TPO and G-CSF did not influence the observed recovery patterns. To test the hypothesis that the limited number of cells transplanted or the subset chosen was responsible for the lack of effectiveness of TPO, three additional monkeys were transplanted with 10(7)/kg unfractionated autologous bone marrow cells. Two of these animals received TPO and the other served as a control. In this setting, as well, TPO treatment did not prevent thrombocytopenia. This study demonstrates that treatment with TPO does not accelerate platelet reconstitution from transplanted stem cells after high-dose TBI. These findings contrast with the rapid TPO-stimulated platelet recovery in myelosuppression induced by 5 Gy of TBI in rhesus monkeys; we conclude from this that the clinical effectiveness of the TPO response depends on the availability of TPO target cells in the first week after TBI, that is, before endogenous TPO levels reach the saturation point. In addition, protracted isolated thrombocytopenia was observed in two G-CSF-treated monkeys, one of which also received TPO. Furthermore, TPO treatment for 7 days in the 6th week after TBI during severe thrombocytopenia in one monkey produced prompt clinical improvement and an increase in platelet counts.
在一项安慰剂对照研究中，评估了重组人血小板生成素（TPO）和重组人粒细胞集落刺激因子（G-CSF）对刺激血小板和中性粒细胞恢复的疗效。该研究将数量有限（1-3×10⁴/kg）的高度纯化自体干细胞（CD34++/RhLA-DR[弱阳性]）移植到恒河猴体内，这些动物先接受8 Gy的全身照射（TBI）（X射线）。移植缩短了由严重TBI引起的全血细胞减少期，从5至6周缩短至3周。每日皮下注射TPO（10μg/kg/天，TBI后第1-21天），无论单独使用还是与G-CSF（5μg/kg/天皮下注射，TBI后第1-21天）联合使用，均未刺激移植后血小板再生。G-CSF治疗未能预防猴子的中性粒细胞减少，也未刺激中性粒细胞水平恢复正常。同时给予TPO和G-CSF不影响观察到的恢复模式。为了检验移植细胞数量有限或所选细胞亚群导致TPO无效的假设，另外三只猴子移植了10⁷/kg未分级的自体骨髓细胞。其中两只动物接受TPO治疗，另一只作为对照。在这种情况下，TPO治疗也未能预防血小板减少。这项研究表明，TPO治疗不能加速高剂量TBI后移植干细胞的血小板重建。这些发现与恒河猴5 Gy TBI诱导的骨髓抑制中TPO刺激的快速血小板恢复形成对比；我们由此得出结论，TPO反应的临床有效性取决于TBI后第一周，即内源性TPO水平达到饱和点之前TPO靶细胞的可用性。此外，在两只接受G-CSF治疗的猴子中观察到持续性孤立性血小板减少，其中一只还接受了TPO治疗。此外，在一只猴子严重血小板减少的TBI后第6周，给予TPO治疗7天，临床症状迅速改善，血小板计数增加。
