The Role of Nitric Oxide in Graft-Versus-Tumor Effect

Yim, Chang Yeol; Choi, Jung Ki; Sohn, Myung Hee; Kwak, Jae Yong

Abstract

BACKGROUND
Nitric oxide (NO) synthesis by inducible nitric oxide synthase (iNOS) is induced during graft-versus-host disease (GVHD). It is yet unknown whether NO has any roles in graft-versus-tumor effect (GVT) which is often associated with GVHD. The present study was performed to test the role of NO in GVT.
METHODS
GVT was induced by tail vein injection of C57BL/6J (H-2b) mouse splenocytes (10(8)cells/mouse) to [C57BL/6J (H-2(b))XBALB/c (H-2(d))] F1 mice bearing Meth-A (H-2d) ascites tumors.
RESULTS
Induction of GVT increased nitrite production (21.0+/-4.1 M) and expression of iNOS protein and mRNA by cells derived from ascites. The increased nitrite production was inhibited by NG-monomethyl-L-arginine (MLA). Immunomagnetic depletion of Mac-1+ cells from ascites cells of GVT mice resulted in a 70% decrease in the nitrite production, indicating that macrophages were implicated as a major cellular source of the nitrite production. Interferon-gamma (IFNgamma) levels in both serum and ascites fluid were markedly increased during GVT. Induction of GVT in ascites tumor-bearing mice prolonged survival from 9.5+/-2.2days to 17.6+/-1.2 days (P<0.001), and increased urinary nitrate excretion up to threefold. MLA administration effectively inhibited the GVT-induced urinary nitrate excretion and further prolonged the GVT-induced increase in survival from 17.6+/-1.2days to 23.6+/-1.9days (P<0.001).
CONCLUSION
These results indicate that NO synthesis by iNOS is induced in tumor tissues during GVT, and the NO acts as an inhibitor mechanism of GVT.