Chronic schistosomiasis is an infectious disease characterized by a granulomatous response which undergoes predictable modifications as a consequence on the appearance of a suppressor pathway (modulation). This proposal seeks to investigate the key role of the mononuclear phagocytes in the schistosome granuloma and will focus on their phenotype and functions, as well as on the complex macrophage-lymphocyte interactions that may underlie the process of modulation. Mice will be infected with cercariae of Schistosoma mansoni, and macrophages from egg-induced hepatic granulomas will be isolated at critical times to allow comparative studies before and after immunomodulation. Granuloma macrophages will be tested by exploring their ability to a) promote antigen specific T cell proliferation in vitro as well as b) induce hypersensitivity in vivo, in systems involving hapten, protein and specific egg antigens, which will be related to their expression of determinants encoded by the I-A subregion of the major histocompatibility complex. The role of granuloma macrophages in the induction of immunosuppression will be initially tested in a well characterized system involving the hapten 4-hydroxy-3-nitrophenyl acetyl (NP). Differences in the induction of immunosuppression between pre and post-modulation macrophages will be correlated with a) expression of I-J subregion determinants, b) state of activation measured by C3-mediated phagocytosis and expression of 5 feet nucleotidase, c) secretion of stimulatory and inhibitory molecules (lymphocyte stimulating factor and macrophage-derived suppressor factor, and d) macrophage-mediated cytotoxicity. Studies on egg antigen-specific suppression in vivo, induced by granuloma macrophages, will a) outline the nature and characteristics of suppressor macrophages, b) determine antigen specificity and H-2 restriction, as well as c) establish the duration of the state of suppression, by assessing its effect, in schistosome-infected mice, on the number and size of hepatic egg granulomas as well as on survival. This model offers a unique opportunity for improved understanding of spontaneous immunoregulation and the role it plays in determining the course of parasitic disease.
Showing the most recent 10 out of 32 publications
