Schistosomiasis causes pathology in an estimated 190 million individuals. Clinical disease is caused by a complex immunopathologic response to the parasite ova, which are deposited in the host tissues. This immunopathologic response is composed of two major elements, granulomas and hepatic fibrosis. These two elements are regulated by discrete populations of T lymphocytes through the production of inflammatory cytokines and growth factors. Therefore methods designed to influence T cell activation and subsequent cytokine release may reduce immunopathology. However, these approaches often are predicted on restricted T cell gene usage, genetic restriction, and precise epitopic definition. Therefore, the practicality of these approaches is limited in the human population because of the genetic heterogeneity of the human immune response. We propose to study a fusion toxin, DAB-IL-2. This mode of immunosuppression is not genetically restricted and preferentially attacks Schistosoma mansoni, Soluble Egg Antigen specific activated T cells. DAB-IL-2 is a Diphtheria toxin-IL-2 chimeric protein. When SEA activated T cells, the cells express the IL_2 high affinity receptor. The receptor binds the toxin and internalizes it. The cells are inactivated or killed and are no longer able to participate in the induction and/or the maintenance of egg-associated immunopathology. This approach provides a model which is relatively independent of genetic restriction and precise epitopic definition. DAB-IL-2 fusion toxin will be used to prevent the development and/or promote the resolution of immunopathology. We will define the efficacy, safety, and mechanisms of action of DAB-IL-2 in murine schistosomiasis mansoni. The mechanisms of suppression will be defined by studies on clonal deletion and subpopulation/cytokine regulation. DAB-IL-2 has been used safely and successfully in man to treat rheumatoid arthritis and juvenile onset diabetes mellitus. The immunopathology of these diseases has many analogies to the immunopathology of schistosomiasis. These studies will provide information on the genesis and treatment of schistosomiasis and facilitate the targeted reduction of immunopathology in man.
