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 di sease (GVHD) was investigated in a murine bone marrow (BM) transplanta tion model where donor and recipient were H-2-matched but differed at multiple minor histocompatibility antigens. Host AKR/J (H-2(K)) mice r eceived lethal total body irradiation as pretransplant conditioning fo llowed by transplantation of donor B10.BR (H-2(K)) BM cells with or wi thout 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 sev ere GVHD. Administration of N-G-methyl-L-arginine (L-NMA), an inhibito r of nitric oxide synthase, to animals undergoing GVHD resulted in eff ective suppression of NO production when compared with saline-treated GVHD control animals. Suppression of NO production by L-NMA in GVHD an imals was associated with enhanced weight loss early posttransplant an d decreased overall survival. Histologic analysis of tissues from L-NM A-treated and saline-treated GVHD animals showed that early weight los s was not because of an exacerbation of GVHD, indicating that NO did n ot appear to play an immunosuppressive role in this experimental model . L-NMA-treated animals with enhanced weight loss were observed to hav e splenic atrophy, decreased extramedullary hematopoiesis, and a reduc tion 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 a ssess the role of NO on BM progenitor cell growth. L-NMA added directl y into culture had no effect on CFU-granulocyte/macrophage (CFU-GM) fo rmation in normal murine BM. In contrast, total CFU-GM from L-NMA-trea ted animals were significantly reduced when compared with GVHD control s or BM control animals who did not develop GVHD. Collectively, these data indicate that inhibition of NO impairs hematopoietic reconstituti on and support the premise that NO appears to play a novel role in the facilitation of alloengraftment posttransplant. (C) 1994 by The Ameri can Society of Hematology.