Nitric oxide mediation of active immunosuppression associated with graft-versus-host reaction.
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-gamma (IFN-gamma)-dependent and affects both T-cell proliferative responses and thymus-independent antibody production by CD5(+) B cells; and a second, which is IFN-gamma-independent and affects B-cell proliferative responses. Because IFN-gamma 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, N(G)-monomethyl-L-arginine [LMMA]), like anti-IFN-gamma 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-gamma-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.
INSERM Unité 267 "Immunogénétique des Allogreffes", Hôpital Paul Brousse, Villejuif Cedex, France. bobe@infobiogen.fr
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Bobé
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Benihoud
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Grandjon
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Opolon
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Pritchard
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Huchet
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006087:Graft vs Host Reaction / Q000276:immunology*; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000276:immunology; D052247:Nitric Oxide Synthase Type II
D004791:Enzyme Inhibitors; D015778:Minor Histocompatibility Antigens; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse