title: Bone marrow transplantation from Fv-4-resistant donors rescues Friend leukemia virus-infected mice from leukemia: a model of bone marrow transplantation therapy against retroviral infection.
abstract: 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.
authors: Division of Physiology and Pathology, National Institute of Radiological Sciences, Chiba, Japan.
authors: M
authors: M
authors: Kitagawa
authors: H
authors: H
authors: Kamisaku
authors: S
authors: S
authors: Aizawa
authors: T
authors: T
authors: Sado
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005622:Friend murine leukemia virus; D007113:Immunity, Innate / Q000235:genetics*; D007942:Leukemia, Experimental / Q000235:genetics / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011828:Radiation Chimera; D012192:Retroviridae Infections / Q000235:genetics / Q000628:therapy*; D018183:Transplantation Chimera; D014412:Tumor Virus Infections / Q000235:genetics / Q000628:therapy*