Kitagawa M, Kamisaku H, Aizawa S, Sado T
Division of Physiology and Pathology, National Institute of Radiological Sciences, Chiba, Japan.
Leukemia. 1994 Dec;8(12):2200-6.
Bone marrow transplantation experiments were conducted in mice in order to develop an experimental bone marrow transplantation therapy model, with which to investigate possible means to cure retrovirus-infected hosts with bone marrow or stem cells from virus-resistant donors. In one experiment, lethally irradiated Friend leukemia virus (FLV)-sensitive C3H/He (C3H; Fv-2s, Fv-4s, Rfv-1s, Rfv-2s Rfv-3s) mice were transplanted with (i) bone marrow cells from FLV-resistant BALB/c-Fv-4Wr (C4W; Fv-2s, Fv-4r, Rfv-1s, Rfv-2s, Rfv-3s) mice (C4W --> C3H) or (ii) a mixture of bone marrow cells from C4W and C3H mice (C4W + C3H --> C3H). They were then inoculated with FLV 3-4 months later and leukemia development was examined. The results indicated that C4W --> C3H chimeras were completely resistant to FLV-induced leukemogenesis and that C4W + C3H --> C3H mixed chimeras that contained as low as 30% C4W-derived cells, or as high as 70% C3H-derived cells, did not develop leukemias. In another experiment, bone marrow cells from C57BL/6 (B6; Fv-2r, Fv-4s, Rfv-1r, Rfv-2r, Rfv-3r) or C4W donors were grated to FLV-sensitive DBA/2 mice (DBA; Fv-2s, Fv-4s, Rfv-1s, Rfv-2s, Rfv-3s) that had been infected with FLV 6 days earlier (DBA-FLV). The results indicated that most, if not all, FLV-infected DBA mice which received bone marrow transplantation from B6 donors developed B6-derived leukemias, although the survival time of these mice was dramatically prolonged as compared to that of untreated DBA-FLV mice. In contrast, bone marrow transplantation from Fv-4r-bearing C4W donors successfully rescued FLV-infected DBA mice from leukemic deaths. Thus, the bone marrow transplantation therapy against retroviral infection of hemopoietic cells was shown to be feasible, provided that donor cells carry a resistant allele that functions via receptor blockade as in the case of Fv-4r, but less effective when the roles of the resistant alleles partially interfered with the virus replication, leukemic transformation and/or cycling of target cells as suggested for Fv-2r gene action, or to resist virus infection by immunological means as are known for Rfv-1r, Rfv-2r and Rfv-3r genes which are also carried by B6-strain mice. Implication of these findings on the somatic gene therapy against retrovirus infection diseases in man are discussed.
为了建立一种实验性骨髓移植治疗模型，从而研究用来自抗病毒供体的骨髓或干细胞治愈逆转录病毒感染宿主的可能方法，在小鼠身上进行了骨髓移植实验。在一项实验中，对经致死剂量照射的对弗氏白血病病毒（FLV）敏感的C3H/He（C3H；Fv-2s、Fv-4s、Rfv-1s、Rfv-2s、Rfv-3s）小鼠进行如下移植：（i）来自抗FLV的BALB/c-Fv-4Wr（C4W；Fv-2s、Fv-4r、Rfv-1s、Rfv-2s、Rfv-3s）小鼠的骨髓细胞（C4W→C3H），或（ii）来自C4W和C3H小鼠的骨髓细胞混合物（C4W + C3H→C3H）。然后在3 - 4个月后给它们接种FLV，并检查白血病的发展情况。结果表明，C4W→C3H嵌合体对FLV诱导的白血病发生完全有抗性，并且含有低至30% C4W来源细胞或高达70% C3H来源细胞的C4W + C3H→C3H混合嵌合体未发生白血病。在另一项实验中，将来自C57BL/6（B6；Fv-2r、Fv-4s、Rfv-1r、Rfv-2r、Rfv-3r）或C4W供体的骨髓细胞移植到6天前已感染FLV的对FLV敏感的DBA/2小鼠（DBA；Fv-2s、Fv-4s、Rfv-1s、Rfv-2s、Rfv-3s）（DBA-FLV）体内。结果表明，大多数（如果不是全部）接受来自B6供体骨髓移植的FLV感染DBA小鼠发生了B6来源的白血病，尽管与未治疗的DBA-FLV小鼠相比，这些小鼠的存活时间显著延长。相比之下，来自携带Fv-4r的C4W供体的骨髓移植成功挽救了FLV感染的DBA小鼠免于白血病死亡。因此，已证明针对造血细胞逆转录病毒感染的骨髓移植治疗是可行的，前提是供体细胞携带一个抗性等位基因，该等位基因通过受体阻断发挥作用，如Fv-4r的情况，但当抗性等位基因的作用部分干扰病毒复制、白血病转化和/或靶细胞循环时（如Fv-2r基因作用所提示的）效果较差，或者像B6品系小鼠也携带的Rfv-1r、Rfv-2r和Rfv-3r基因那样通过免疫手段抵抗病毒感染时效果也较差。讨论了这些发现对人类逆转录病毒感染疾病的体细胞基因治疗的意义。
