Down J D, Tarbell N J, Thames H D, Mauch P M
Department of Radiobiology, State University of Groningen, The Netherlands.
Blood. 1991 Feb 1;77(3):661-9.
Murine bone marrow chimera models were used to assess the efficacy of host total body irradiation (TBI) given at different doses, dose rates, and fractionation schemes in providing for engraftment of syngeneic and allogeneic bone marrow. B6-Hbbd congenic and LP mice, respectively, were used as donors (10(7) bone marrow cells) for syngeneic and allogenic (H-2 compatible) transplantation in standard B6 recipients. Stable marrow chimerism was determined from host and donor stem cell-derived hemoglobin phenotypes (Hbbs and Hbbd) on gel electrophoresis at 3 months posttransplant. Partial engraftment of syngeneic marrow was seen at single doses as low as 2 Gy, with the donor component increasing steadily with increasing TBI dose to a level of 100% at 7 Gy. Immunologic resistance of the host appeared to prevent allogeneic engraftment until 5.5 Gy. A very steep radiation dose response was then observed so that the level of chimerism with 6 Gy and above became comparable with syngeneic engraftment. Low dose rate (5 cGy minute-1) and fractionated TBI required higher total doses for equivalent engraftment (radiation dose-sparing) in both syngeneic and allogenic bone marrow transplantation. This displacement in the dose-response curve on fractionation was seen with interfraction intervals of 3 and 6 hours. A further dose-sparing effect was observed on extending the interval to 18 and 24 hours, but only for allogeneic transplantation, and may therefore be related to recovery of immune-mediated graft resistance. The involvement of multiple target cell populations in determining allogenic engraftment rendered the application of the linear-quadratic model for radiation cell survival problematic in this case. The recovery in dose when low dose rate and 6-hour interfraction intervals were applied in either syngeneic or allogeneic BMT is consistent with appreciable sub-lethal damage repair in the primitive self-renewing stem cell population of the host marrow. These results contrast with the poor repair capacity of the 11-day spleen colony-forming units (CFUs) population after fractionated irradiation and support the notion that ablation of early stem cells in the pre-CFUs compartment is essential for long-term marrow engraftment.
采用小鼠骨髓嵌合体模型，评估不同剂量、剂量率和分割方案的宿主全身照射（TBI）在促进同基因和异基因骨髓植入方面的效果。分别使用B6-Hbbd同源基因小鼠和LP小鼠作为供体（10⁷个骨髓细胞），用于在标准B6受体中进行同基因和异基因（H-2相容）移植。在移植后3个月，通过凝胶电泳检测宿主和供体干细胞衍生的血红蛋白表型（Hbbs和Hbbd）来确定稳定的骨髓嵌合状态。同基因骨髓在低至2 Gy的单次剂量下可见部分植入，随着TBI剂量增加，供体成分稳步增加，在7 Gy时达到100%的水平。宿主的免疫抗性似乎会阻止异基因植入，直到5.5 Gy。随后观察到非常陡峭的辐射剂量反应，因此6 Gy及以上的嵌合水平与同基因植入相当。低剂量率（5 cGy分钟⁻¹）和分割TBI在同基因和异基因骨髓移植中需要更高的总剂量才能实现等效植入（辐射剂量节省）。在3小时和6小时的分次间隔下，观察到分次照射时剂量反应曲线的这种位移。将间隔延长至18小时和24小时时观察到进一步的剂量节省效应，但仅适用于异基因移植，因此可能与免疫介导的移植物抗性恢复有关。在这种情况下，多个靶细胞群体参与确定异基因植入使得线性二次模型在辐射细胞存活方面的应用存在问题。在同基因或异基因骨髓移植中应用低剂量率和6小时分次间隔时剂量的恢复与宿主骨髓原始自我更新干细胞群体中明显的亚致死损伤修复一致。这些结果与分次照射后11天脾集落形成单位（CFU）群体的修复能力差形成对比，并支持以下观点，即CFU前区室中早期干细胞的消融对于长期骨髓植入至关重要。
