title: Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome.
abstract: In chronic inflammation, macrophages and neutrophils, which are derived from bone marrow, play a pivotal role. Therefore, reconstitution of bone marrow with anti-inflammatory stem cells may modify inflammation. In this study, transplantation-based gene therapy was applied to glomerular inflammation for a long-lasting suppression of the glomerular damage seen in chronic nephritis. Bone marrow cells were harvested from male donor mice, which had received 5-fluorouracil 3 days previously, and transduced with an interleukin 1 (IL-1) receptor antagonist (IL-1Ra) or a mock gene using a retrovirus vector. After confirmation that transduced cells possessed the transgene at approximately 0.7 copies per cell and secreted recombinant IL-1Ra, these cells were infused into sublethally irradiated (6 Gy) female recipients once daily for 4 consecutive days. These female recipient mice had the male Y antigen in bone marrow, liver, and spleen, and 10% to 20% of their spleen cells possessed the transgene even 8 weeks after transplantation. Glomerulonephritis was then induced in these mice. Renal function and histology were retarded in the mice whose bone marrow was reconstituted with IL-1Ra-producing cells compared with mock transduced cells. In situ hybridization using a Y painting probe revealed that transplanted donor cells were recruited into the glomerulus upon induction of nephritis, suggesting therapeutic effects were channeled through the secretion of IL-1Ra from these cells. Furthermore, the survival rate after a second challenge with nephrotoxic antibody was significantly improved in the IL-1Ra chimera. These results suggest that reconstitution of bone marrow for continuous supply of anti-inflammatory cells may be a useful strategy for the treatment of chronic inflammation.
authors: Department of Internal Medicine, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan. tyokoo@jikei.ac.jp
authors: T
authors: T
authors: Yokoo
authors: T
authors: T
authors: Ohashi
authors: Y
authors: Y
authors: Utsunomiya
authors: J S
authors: JS
authors: Shen
authors: Y
authors: Y
authors: Hisada
authors: Y
authors: Y
authors: Eto
authors: T
authors: T
authors: Kawamura
authors: T
authors: T
authors: Hosoya
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000628:therapy*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D003401:Creatine / Q000187:drug effects / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005921:Glomerulonephritis / Q000139:chemically induced / Q000628:therapy; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009584:Nitrogen / Q000652:urine; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D015996:Survival Rate; D014161:Transduction, Genetic
chemical_list: D000893:Anti-Inflammatory Agents; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D003401:Creatine; D009584:Nitrogen