Genetically modified bone marrow continuously supplies anti-inflammatory cells and suppresses renal injury in mouse Goodpasture syndrome

In chronic inflammation, macrophages and neutrophils, which are derived fro m bone marrow, play a pivotal role. Therefore, reconstitution of bone marro w 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 nep hritis, Bone marrow cells were harvested from male donor mice, which had re ceived 5-fluorouracil 3 days previously, and transduced with an interleukin 1 (IL-1) receptor antagonist (IL-1Ra) or a mock gene using a retrovirus ve ctor. After confirmation that transduced cells possessed the transgene at a pproximately 0.7 copies per cell and secreted recombinant IL-1Ra, these cel ls were infused into sublethally irradiated (6 Gy) female recipients once d aily for 4 consecutive days. These female recipient mice had the male Y ant igen in bone marrow, liver, and spleen, and 10% to 20% of their spleen cell s possessed the transgene even 8 weeks after transplantation. Glomeruloneph ritis was then induced in these mice. Renal function and histology were ret arded 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. Furthermor e, the survival rate after a second challenge with nephrotoxic antibody was significantly improved in the IL-1Ra chimera. These results suggest that r econstitution of bone marrow for continuous supply of anti-inflammatory cel ls may be a useful strategy for the treatment of chronic inflammation. (C) 2001 by The American Society of Hematology.