We have discovered that an attenuated Salmonella vaccine induces superior levels of protection in mice against challenge with virulent Salmonella, tumoricidal and Leishmaniacidal macrophages, and paradoxically at the same time induces profound immunosuppression of splenic mitogenic and in vitro plaque-forming cell responses. We have shown suppression is active, is mediated by a non-H-@ restricted soluble factor, secreted by two populations of cells: adherent, phagocytic, esterase-positive macrophages, and a second, newly defined population of nonadherent, nonphagocytic, esterase-negative cells that contains 75% mononuclear cells with the characteristics of macrophage precursors. We have shown that suppression is reversed by alphaIFNgamma, by IL-4, and by an inhibitor of reactive nitrogen intermediates (RNI), N-monomethyl L-arginine. Suppressor cells produce RNI in culture, and the three inhibitors of suppression also suppress nitrite accumulation. Thus, nitric oxide or another RNI is induced by the attenuated Salmonella and acts as a suppressor factor. As nitric oxide is also a known tumoricidal and microbicidal factor (for eukaryotic pathogens) secreted by activated macrophages, the hypothesis is formulated that Salmonella induce effector cells which mediate protection and suppression through nitric oxide. It is proposed to further investigate these phenomena by 1) identifying more definitively the suppressor and effector cells in the spleen and peritoneal cavity induced by attenuated Salmonella, and seeing if they are the same or different; 2) examining the cellular and cytokine pathway(s) required for induction of suppression and suppressor cells, and testing if they are similar to or different from the pathways leading to protection and to tumoricidal, microbicidal and NK effector cells; 3) determining the target cell(s) of the macrophage suppressor factor and the nature of the blockage in the cellular and cytokine pathways which normally lead to immune responses; and 4) correlating the capacity of Salmonella vaccines to protect and to suppress with production of reactive nitrogen intermediates (RNI) and reactive oxygen intermediates (ROI). The proposed studies on mechanisms of suppression induced by attenuated Salmonella have application to development of vaccines, as suppression post vaccination may be an unwanted side-effect of inoculation. In a broader context, the studies are of basic interest as they will further define the properties of a population of cells in the monocyte/macrophage lineage which are known to be suppressive, but which could also be effector cells. These same cells may be induced by other inflammatory stimuli that result in a mononuclear response. Thus, these studies may elucidate fundamental relationships between suppressive and potentiating effects of a variety of infectious agents and biological response modifiers.
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