MACROPHAGE NITRIC-OXIDE MEDIATES IMMUNOSUPPRESSION IN INFECTIOUS INFLAMMATION

A vaccine strain of live, attenuated Salmonella typhimurium induces pr ofound immunosuppression in inoculated mice 7 days after injection. Im munosuppression to mitogens and inability to mount plaque-forming resp onses to sheep red blood cells occurs in spite of many parameters of u pregulated macrophage function and protection against challenge with v irulent Salmonella. Studies show that macrophage nitric oxide mediates the immunosuppression and presumably also the early-onset protective capacity of the vaccine. A model of ''bystander lymphocyte aurotoxicit y'' is presented to explain the mechanism of immunosuppression. The mo del proposes that Salmonella-activated macrophages generate nitric oxi de which inactivates lymphocytes in the vicinity, so they become dysfu nctional. Inhibition of nitric oxide by N-G-monomethyl-L-arginine reve rses immunosuppression. Evidence is presented that supports a relation ship between the microbial burden in the spleen, the degree of nitric oxide produced, and the extent of immunosuppression. It is proposed th at this model of microbial Immunosuppression mediated by nitric oxide is generalizable for understanding immunosuppression and loss of delay ed-type hypersensitivity induced by other microbes, such as Mycobacter ia and and measles virus. The model could account for anergy during my cobacterial infections, particularly when the burden of acid-fast baci lli is high, as well as loss of skin test reactivity to tuberculin dur ing measles infection.