Host conditioning with 5-fluorouracil and kit-ligand to provide for long-term bone marrow engraftment
Host conditioning with 5-fluorouracil and kit-ligand to provide for long-term bone marrow engraftment
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DOI：
10.1182/blood.v89.7.2376
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发表时间：
1997-04-01
期刊：
影响因子：
20.3
通讯作者：
Mauch, PM
中科院分区：
文献类型：
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作者：
vanOs, R;Dawes, D;Mauch, PM
在5-氟尿嘧啶（5-FU）给药之前和之后给予试剂盒配体（KL）导致小鼠骨髓衰竭，可能是因为KL诱导的干细胞循环增强，这使它们更容易受到5-FU的影响。为了利用这种对干细胞的作用，我们研究了KL和5-FU在C57 BL/6（B6）小鼠模型中使同源标记的骨髓稳定植入供体的能力。KL以50 μ g/kg皮下给药，在给BG受体间隔7天给予两次剂量的5-FU（125 mg/kg）之前21小时和9小时以及之后3小时。然后在第二次5-FU给药后24、48和72小时，动物接受三次注射10（7）个同源B6-Gpi-1（a）供体骨髓细胞。另一组动物在最后一次5-FU给药后24小时接受1 × 10（7）或3 × 10（7）供体骨髓细胞的单次给药。在1、3、6和8个月时通过红细胞（RBC）中的Gpi表型分析以及在8个月时通过胸腺、脾脏和骨髓中的细胞表型分析测量植入水平。RBC中的供体植入百分比在6个月后似乎稳定。KL + 5-FU制备的受者在8个月时RBC中的供体植入百分比（33.0 +/-2.7）显著高于单独5-FU（18.5 +/-2.6，P <0.0005）或盐水对照（17.8 +/-1.7，P <0.0001）。在另一项实验中，将粒细胞集落刺激因子（100 μ g/剂）加入到降低剂量的KL（12.5 μ g/剂）中;植入与单独KL相似。在移植后8个月，其他组织如骨髓、脾和胸腺中的植入水平与红系细胞植入密切相关，表明这些动物中已植入多能长期再生干细胞。有人担心全身照射（TBI）或白消安为基础的方案在同基因或转导的自体骨髓移植纠正遗传疾病的年轻收件人的毒性。在这些受者中，可能不需要完全的供体植活。KL和5-FU的结果对于进一步完善非TBI、非白消安技术以实现稳定的混合嵌合体是令人鼓舞的。(C)1997年，美国血液学会。
Administration of kit-ligand (KL) before and after doses of 5-fluorouracil (5-FU) results in marrow failure in mice, presumably because of enhanced KL-induced cycling of stem cells, which makes them more susceptible to the effects of 5-FU. In attempt to capitalize on this effect on stem cells, we studied the ability of KL and 5-FU to allow stable donor engraftment of congenically marked marrow in a C57BL/6 (B6) mouse model. KL was administered subcutaneously at 50 mu g/kg, 21 hours and 9 hours before and 3 hours after each of two doses of 5-FU (125 mg/kg) given 7 days apart to BG-recipients. Animals then received three injections of 10(7) congenic B6-Gpi-1(a)-donor bone marrow cells at 24, 48, and 72 hours after the second 5-FU dose. A separate group of animals received a single dose of either 1 x 10(7) or 3 x 10(7) donor marrow cells 24 hours after the last 5-FU dose. The level of engraftment was measured from Gpi-phenotyping at 1, 3, 6, and 8 months in red blood cells (RBCs) and at 8 months by phenotyping cells from the thymus, spleen, and marrow. Percent donor engraftment in RBCs appeared stable after 6 months. The percent donor engraftment in RBCs at 8 months was significantly higher in KL + 5-FU prepared recipients (33.0 +/- 2.7), compared with 5-FU alone (18.5 +/- 2.6, P < .0005), or saline controls (17.8 +/- 1.7, P < .0001). In an additional experiment, granulocyte colony-stimulating factor (100 mu g/dose) was added to a reduced dose of KL (12.5 mu g/dose); engraftment was similar to KL alone. At 8 months after transplantation the levels of engraftment in other tissues such as bone marrow, spleen, and thymus correlated well with erythroid engraftment to suggest that multipotent long-term repopulating stem cells had engrafted in these animals. There are concerns for the toxicity of total body irradiation (TBI)- or busulfan-based regimens in young recipients of syngeneic or transduced autologous marrow who are transplanted for correction of genetic disease. In these recipients complete donor engraftment may not be needed. The results with KL and 5-FU are encouraging for the further refinement of non-TBI, nonbusulfan techniques to achieve stable mixed chimerism. (C) 1997 by The American Society of Hematology.