A crucial question in the study of tumor neuro-immunology concerns the capacity of the central nervous system to initiate and execute an immune response. In a 100 percent fatal rat malignant glioma model, genetically-modified tumors secreting INF-'intracerebrally generate an immune response resulting in a substantial increase in survival time, tumor rejection, and specific systemic immunity. IL-2 secreted by genetically-modified tumors does not change the biologic behavior of transfected gliomas. INF-' induces elevated expression of major histocompatibility complex class I and class II molecules in microglia throughout the brain and invokes enhanced tumor infiltration by CD4, CD8, and NK cells. These findings demonstrate the successful immunization against a central nervous system tumor by direct priming in the brain with a live growth-competent tumor vaccine. The broad and long term objectives of this research are to clarify the basic principles responsible for the initiation of an immune response after priming in the brain, and to devise novel immunotherapeutic strategies for the treatment of patients with malignant brain tumors. The specific research proposed in this application is intended to examine the capacity of microglia to function as competent antigen presenting cells to tumor specific antigens, and the role of major histocompatibility antigen class I/II molecules and CD4/CD8 cells in the initiation of such an immune response. The importance and health relevance of this research are exemplified by our therapeutic results in animals showing that, in a universally fatal brain tumor model, 95 percent of the rats implanted intracerebrally with INF-'-secreting tumors survive substantially longer than controls, and 43 percent reject the tumor and develop protective systemic immunity. The results of the proposed research will provide conclusive evidence whether microglia are responsible for presenting CNS-derived tumor antigens, and are crucial for designing future immunotherapeutic strategies for the treatment of patients with either primary or metastatic brain tumors.
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