Genes controlling macrophage activation appear to play a critical role in protective immunity against challenge Schistosoma mansoni infection in mice sensitized by primary infection or vaccination with irradiated cercariae. This proposal aims to determine in what way(s) the function of these genes controls expression of resistance, using techniques of cellular immunology and immunogenetics. The 3 major functions of macrophages in immune response will be compared in inbred strains of mice previously found to develop high levels of concomitant or vaccine-induced immunity (measured by recovery of challenge parasites) and in macrophage-deficient strains found to develop low levels of resistance. Macrophage accessory cell function will be assessed by the ability of cells to process and present antigens in an immunogenic form to lymphocytes in vitro and by development of delayed hypersensitivity and antibody responses in vivo. Effector cell function will be examined as the ability of macrophages activated as a result of specific anti-S. mansoni immune response, or their products, to damage schistosomes. The ability of specific antigen-responsive (lymphokine producing) T lymphocytes to transfer immunity will also be tested. Immunoregulatory function, by virtue of inhibitory products such as prostaglandins or by antigen presentation in a way that stimulates suppressor T cells, will be examined. In addition, since genes controlling macrophage activation are not yet identified and only functionally defined, and therefore may control resistance through mechanisms not directly involving macrophages, levels of other responses proposed to influence resistance (eg. egg-related pathology, granulocytosis) will be monitored. Initial analyses will allow detection of any abnormalities in low responder (non-resistant) mice, and thus reveal those responses that may be relevant to immunity. These reactivities will then be examined in immunized backcross (low responder x F1) animals. Positive reactivity will be correlated with the ability to resist challenge infection in individual mice; linkage analysis will allow final identification of responses crucial to resistance. This knowledge should facilitate design of a simpler vaccine protocol in which immune responses of proven protective value can be invoked by stimulation with non-living antigens.
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