Inhibition of nitric oxide production is associated with enhanced weight loss, decreased survival, and impaired alloengraftment in mice undergoing graft-versus-host disease after bone marrow transplantation.
The pathophysiologic role of nitric oxide (NO) in graft-versus-host disease (GVHD) was investigated in a murine bone marrow (BM) transplantation model where donor and recipient were H-2-matched but differed at multiple minor histocompatibility antigens. Host AKR/J (H-2K) mice received lethal total body irradiation as pretransplant conditioning followed by transplantation of donor B10.BR (H-2K) BM cells with or without spleen cells as a source of GVH-reactive T cells. NO production, as assessed by serum nitrate and nitrite levels, was increased for up to 3 weeks posttransplant in animals undergoing both moderate and severe GVHD. Administration of NG-methyl-L-arginine (L-NMA), an inhibitor of nitric oxide synthase, to animals undergoing GVHD resulted in effective suppression of NO production when compared with saline-treated GVHD control animals. Suppression of NO production by L-NMA in GVHD animals was associated with enhanced weight loss early posttransplant and decreased overall survival. Histologic analysis of tissues from L-NMA-treated and saline-treated GVHD animals showed that early weight loss was not because of an exacerbation of GVHD, indicating that NO did not appear to play an immunosuppressive role in this experimental model. L-NMA-treated animals with enhanced weight loss were observed to have splenic atrophy, decreased extramedullary hematopoiesis, and a reduction in BM cellularity when compared with GVHD control mice that were weight-matched before transplant. Analysis of T-cell chimerism in the spleen showed that L-NMA treatment impaired donor T-cell repopulation. In vitro colony-forming unit (CFU) assays were performed to further assess the role of NO on BM progenitor cell growth. L-NMA added directly into culture had no effect on CFU-granulocyte/macrophage (CFU-GM) formation in normal murine BM. In contrast, total CFU-GM from L-NMA-treated animals were significantly reduced when compared with GVHD controls or BM control animals who did not develop GVHD. Collectively, these data indicate that inhibition of NO impairs hematopoietic reconstitution and support the premise that NO appears to play a novel role in the facilitation of alloengraftment posttransplant.
Drobyski
W R
WR
Department of Medicine, Medical College of Wisconsin, Milwaukee 53226.
Keever
C A
CA
Hanson
G A
GA
McAuliffe
T
T
Griffith
O W
OW
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000473:pathology*; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000473:pathology*; D051379:Mice; D008806:Mice, Inbred AKR; D016747:Minor Lymphocyte Stimulatory Antigens / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D019323:omega-N-Methylarginine
D016747:Minor Lymphocyte Stimulatory Antigens; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases