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Inhibition of Inducible Nitric Oxide Synthase Enhances Anti-tumour Immune Responses in Rats Immunized with IFN-gamma-Secreting Glioma Cells.

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Author

Summary, in English

Interferon gamma (IFN-gamma) has successfully been used in immunotherapy of different experimental tumours. Mechanistically, IFN-gamma has extensive effects on the immune system including release of nitric oxide (NO) by upregulation of the inducible nitric oxide synthase (iNOS). NO has putative immunosuppressive effects but could also play a role in killing of tumour cells. Therefore, the aim of the present study was to clarify whether inhibition of iNOS in rats immunized with glioma cells (N32) producing IFN-gamma (N32-IFN-gamma), could enhance the anti-tumour immune response. Initially, both a selective iNOS, L-N-6-(I-Iminoethyl)-L-lysine (L-NIL), and non-selective, N-nitro-L-arginine methyl ester (L-NAME), inhibitor of NOS were tested in vitro. After polyclonal stimulation with LPS and SEA, both L-NIL and L-NAME enhanced proliferation and production of IFN-gamma from activated rat splenocytes and this effect was inversely correlated to the production of NO. However, L-NIL had a broader window of efficacy and a lower minimal effective dose. When rats were immunized with N32-IFN-gamma), and administered NOS inhibitors by intraperitoneal (i.p.) mini-osmotic pumps, only splenocytes of rats treated with L-NIL, but not L-NAME, displayed an enhanced proliferation and production of IFN-gamma when re-stimulated with N32 tumour cells. Based on these findings, L-NIL was administered concurrently with N32-IFN-gamma cells to rats with intracerebral (i.c.) tumours resulting in a prolonged survival. These results show that inhibition of iNOS can enhance an IFN-gamma-based immunotherapy of experimental i.c. tumours implying that NO released after immunization has mainly immunosuppressive net effects.

Publishing year

2007

Language

English

Pages

289-297

Publication/Series

Scandinavian Journal of Immunology

Volume

65

Issue

3

Document type

Journal article

Publisher

Wiley-Blackwell

Topic

  • Immunology in the medical area

Status

Published

ISBN/ISSN/Other

  • ISSN: 1365-3083