Our objective is the development and characterization of monoclonal immune network components capable of modulating granulomatous inflammation in vivo and ameliorate disease in murine S. japonicum. In mice, naturally occurring immune network components mediate immune modulation in vitro; specifically IgG1 antibodies directed toward soluble egg antigens (SEA) and IgG1 anti-idiotypic antibodies which describe a major cross reactive idiotypic (SJ-CRI-M) on anti-SEA molecules.
The specific aim of this proposal is to (1) produce monoclonal antibodies with similar specificities as these naturally occurring polyclonal antisera by somatic cell fusion (2) characterize these monoclonal proteins physiochemically and serologically in terms of SJ-CRI-M (3) use these anti-SEA monoclonals to dissect the antigen(s) responsible for eliciting pathology in murine S. japonicum infection, and (4) test these reagents for their ability to suppress granulomatous inflammation and amelioroate clinical disease. The long term goal is to understand the development of clinical disease in humans with schistosomiasis and develop new immunologic strategies to ameliorate its pathology. Disease in schistosomiasis japonica results from the granulomatous inflammation which occurs around parasite ova trapped in the liver. As infection becomes chronic, a beneficial immunologic adjustment occurs that results in smaller egg granuloma and lower portal pressure. This process, termed modulation is essential to our understanding of disease in man since the majority of humans are chronically infected and asymptomatic. Only a relatively small percentage of infected humans (5-10%) develop hepatosplenomegaly, portal hypertension and bleeding esphageal varicies, the leading cause of death in schistosomiasis. This may be due to a failure of these individuals to modulate their immune response to trapped ova. it may therefore be possible to develop vaccines to prevent disease rather than the usual concept of infection prevention. The present experiments are designed to provide new insights into the development of clinical disease and new theapeutic approaches to the treatment of schistosomiasis. In addition such experiments should add to a growing body of knowledge that suggests that network interactions (idiotypic/anti-idiotypic) play important roles in the immune response to infectious pathogens.
