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Blood, 1 July 2001, Vol. 98, No. 1, pp. 57-64
GENE THERAPY
Genetically modified bone marrow continuously supplies
anti-inflammatory cells and suppresses renal injury in mouse
Goodpasture syndrome
Takashi Yokoo,
Toya Ohashi,
Yasunori Utsunomiya,
Jin Song Shen,
Yutaka Hisada,
Yoshikatsu Eto,
Tetsuya Kawamura, and
Tatsuo Hosoya
From the Department of Internal Medicine, Department of
Gene Therapy, Institute of DNA Medicine, and Department of Pediatrics,
Jikei University School of Medicine, Tokyo, Japan; and Discovery
Research Laboratory, Tanabe Seiyaku, Osaka, Japan.
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.
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