Vriesendorp Huib M
Exp Hematol. 2003 Oct;31(10):844-54. doi: 10.1016/s0301-472x(03)00229-7.
Nuclear warfare research and treatment of radiation accident victims uncovered the potential of hemopoietic stem cell transplants. Prior to transplantation of hemopoietic stem cells patients receive "conditioning" agents: high-dose total-body irradiation and/or high-dose chemotherapy. High-dose conditioning causes at least 20% procedure-related mortality. Recent efforts to reduce procedure-related mortality by the use of low-dose conditioning included low-dose total-body irradiation, immunosuppressive agents, and the replacement of high-dose chemotherapy by donor lymphocytes for graft-vs-tumor effects. Procedure-related mortality remains high (10-30%). Tumor recurrence at 1 year is over 50%. In this review, the aims of conditioning (creation of space, prevention of hemopoietic stem cell rejection, eradication of immune memory, and eradication of tumor cells) are reexamined in those patient and animal studies that explore quantitative and mechanistic conditioning issues. Translational experimental animal models provide the best opportunities for the development of less toxic conditioning agents for human patients and require an analysis of the consequences of the effects of new conditioning agents on host-vs-graft as well as graft-vs-host reactions. Total-body irradiation or other forms of radiation create space, prevent rejection of histocompatible stem cells, and can eliminate immune memory to autoimmune antigens at modest, nontoxic doses. The transplantation of histoincompatible stem cells and the eradication of large loads of tumor cells remain problematic. The therapeutic index of allogeneic stem cell transplants will increase if new conditioning agents are targeted only to those host tissues that need conditioning: hemopoietic system, immune system, and tumor masses. Radiolabeled immunoglobulins are among the most promising new, low-toxicity conditioning agents.
核战争研究以及辐射事故受害者的治疗揭示了造血干细胞移植的潜力。在造血干细胞移植前，患者会接受“预处理”药物：大剂量全身照射和/或大剂量化疗。大剂量预处理导致至少20%的与治疗相关的死亡率。近期通过使用低剂量预处理来降低与治疗相关死亡率的努力包括低剂量全身照射、免疫抑制剂，以及用供体淋巴细胞替代大剂量化疗以产生移植物抗肿瘤效应。与治疗相关的死亡率仍然很高（10 - 30%）。1年时肿瘤复发率超过50%。在本综述中，在那些探索定量和机制性预处理问题的患者及动物研究中，重新审视了预处理的目标（创造空间、预防造血干细胞排斥、消除免疫记忆以及根除肿瘤细胞）。转化实验动物模型为开发对人类患者毒性较小的预处理药物提供了最佳机会，并且需要分析新的预处理药物对宿主抗移植物以及移植物抗宿主反应的影响后果。全身照射或其他形式的辐射可创造空间、防止组织相容性干细胞被排斥，并且在适度的无毒剂量下可消除对自身免疫抗原的免疫记忆。组织不相容干细胞的移植以及大量肿瘤细胞的根除仍然存在问题。如果新的预处理药物仅针对那些需要预处理的宿主组织：造血系统、免疫系统和肿瘤块，那么异基因干细胞移植的治疗指数将会提高。放射性标记的免疫球蛋白是最有前景的新型低毒性预处理药物之一。
