The Role of Nitric Oxide in Graft-Versus-Tumor Effect.
- Author:
Chang Yeol YIM
1
;
Jung Ki CHOI
;
Myung Hee SOHN
;
Jae Yong KWAK
Author Information
1. Department of Internal Medicine, Chonbuk National University Medical School, Chonju, Korea.
- Publication Type:Original Article
- Keywords:
Nitric oxide;
Graft versus tumor effect;
Immunotherapy;
Neoplasms;
Macrophages;
Arginine
- MeSH:
Mice;
Animals
- From:Korean Journal of Hematology
2003;38(1):40-47
- CountryRepublic of Korea
- Language:Korean
-
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.
