Nitric Oxide Mediation of Active Immunosuppression Associated With Graft-Versus-Host Reaction

• Published in: Blood 1999-08, Vol.94 (3), p.1028-1037
• Main Authors: Bobé, Pierre, Benihoud, Karim, Grandjon, Danièle, Opolon, Paule, Pritchard, Linda Louise, Huchet, Roger
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bone marrow, stem cells transplantation. Graft versus host reaction; Enzyme Inhibitors - pharmacology; Graft vs Host Reaction - immunology; Immunosuppression; Interferon-gamma - immunology; Medical sciences; Mice; Minor Histocompatibility Antigens - immunology; Nitric Oxide - immunology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - immunology; Nitric Oxide Synthase Type II; Transfusions. Complications. Transfusion reactions. Cell and gene therapy
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.3.1028.415k24_1028_1037

In the immunosuppression accompanying the lethal systemic graft-versus-host reaction (GVHR) directed against minor histocompatibility antigens in irradiated adult mice, we previously determined that non-T, non-B, L-leucine methyl ester (LME)-sensitive cells were implicated via two different mechanisms: one, which is interferon-γ (IFN-γ)–dependent and affects both T-cell proliferative responses and thymus-independent antibody production by CD5+ B cells; and a second, which is IFN-γ–independent and affects B-cell proliferative responses. Because IFN-γ induces the production of nitric oxide (NO), a potent immunosuppressive molecule, we investigated the involvement of NO in the suppression mediated by the LME-sensitive cells. Inducible NO synthase (iNOS) mRNA, iNOS protein, and the stable end products of iNOS pathway, L-citrulline and nitrite, were detected early in GVHR in LME-sensitive spleen cells taken ex vivo and could be amplified in vitro by T and B mitogens. Inhibition of NO production with arginine analogs (aminoguanidine, NG-monomethyl-L-arginine [LMMA]), like anti–IFN-γ antibodies, reversed suppression of both T-cell responses to concanavalin A and CD5+ B-cell responses, but not of B-cell response to lipopolysaccharides (LPS). The GVHR-associated, IFN-γ–dependent immunosuppression of T-cell proliferation and of antibody synthesis by CD5+ B cells is the consequence of NO production by LME-sensitive cells. Immunohistochemical analyses indicate that these cells belong to the macrophage lineage.