The development of cell-mediated immunity in visceral leishmanisis is thought to be critical both for cure of the disease, and for long-term immunity to reinfection. The request for a Physician Scientist Award outlines a program of study and research designed to equip the investigator with the tools necessary to study the antigenic basis for cellular immunity in this and related diseases. A schedule for Phase I is outlined, including courses in Cell Biology, Biochemistry, Genetics, and Immunology. A research project will be initiated during Phase I, and will be pursued full-time during Phase II. Performance during Phase I, a defense of the research proposal prior to initiating Phase II, and progress reports on research during Phase II will be reviewed by a committee of faculty members. The research proposal stems from the observation that cellular immune responses parallel recovery from visceral leishmaniasis. The antigens responsible for cell-mediated immunity are not known. Leishmania donovani, the protozoan causing the disease, is inoculated into humans as an extracellular promastigote, whereupon it is ingested by mononuclear phagocytes and converts to the intracellular amastigote stage. After recovery from leishmaniasis the host is immune to reinfection, but immunity cannot be induced by vaccination of healthy hosts with killed promastigotes. We will establish first whether immunity to leishmaniasis in mice can be conferred by exposure to live or to fixed parasites in each stage, or to Leishmania-infected macrophages. T cell clones will be raised in immune animals, and the specificity for amastigote or promastigote forms will be established. We will investigate whether these clones can confer delayed type hypersensitivity and immunity in naive mice. Using subcellular fractionation of parasites, the antigenic specificity of these clones will be proved. My goal is the identification of parasite antigens responsible for cell-mediated immmune responses to L. donovani, in an attempt to analyze at a molecular level protective immunity to the disease.
