RRC ID 4781
Author Yokoo T, Ohashi T, Utsunomiya Y, Shen JS, Hisada Y, Eto Y, Kawamura T, Hosoya T.
Title Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome.
Journal Blood
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.
Volume 98(1)
Pages 57-64
Published 2001-7-1
PMID 11418463
MeSH Animals Anti-Glomerular Basement Membrane Disease / therapy* Anti-Inflammatory Agents / administration & dosage* Anti-Inflammatory Agents / pharmacology Bone Marrow Cells / metabolism Bone Marrow Transplantation* Creatine / drug effects Creatine / urine Disease Models, Animal Female Genetic Therapy / methods* Glomerulonephritis / chemically induced Glomerulonephritis / therapy Humans Interleukin 1 Receptor Antagonist Protein Kidney / drug effects Kidney / pathology Male Mice Mice, Inbred DBA Nitrogen / urine Sialoglycoproteins / administration & dosage Sialoglycoproteins / genetics Sialoglycoproteins / pharmacology Survival Rate Transduction, Genetic
IF 16.601
Times Cited 31
DNA material pMFGmIL1RA (RDB1440)