The occurrence of certain AIDS-associated opportunistic infectious diseases for which there is no cure combined with the emergence of multidrug-resistant strains of bacteria and fungi has produced an urgent need for new approaches to antimicrobial therapy. We have recently suggested the use of radioimmunotherapy (RIT) as a novel modality for treatment of opportunistic infections whereby radiolabeled specific antibodies are used to deliver microbicidal radiation to pathogens. A proof of principle for this strategy was achieved by demonstrating that radiolabeled antibodies can be used in the therapy of experimental Cryptococcus neoformans infection. This application proposes to investigate the interaction betweenAIDS-associated opportunistic microorganisms and particulate radiation delivered to the microbial cells by specific antibodies during radioimmunotherapy. Our goal is to carry out basic research studies that will explore fundamental questions related to antimicrobial radioimmunotherapy to further the development of this promising experimental treatment. C. neoformans has several advantages as a model system for radioimmunotherapy of fungal AIDS-associatedopportunistic infections which include the existenceof excellent animal models and the availability of several well characterized immunological reagents. Furthermore, monoclonal antibody (mAb) therapy is already in clinical testing for C. neoformans using the mAb 18B7. We hypothesize that radiolabeled antibodies will be efficient delivery vehicles for targeting radiation to microbial cells. We anticipate that targeted microbes will be killed by RIT through """"""""direct hit"""""""", """"""""cross-fire"""""""" or """"""""bystander"""""""" effects. We also hypothesize that it is possible to eradicate C. neoformans infection in vivo without clinically significant radiation injury to the surrounding tissue and major organs and without damage to the components of immune system.
Three aims are proposed: 1) To investigate the radiobiological mechanisms of interaction between radiolabeled antibodies and fungal cells; 2) To establish correlation between pharmacology, efficacy and toxicity of radioimmunotherapy in animal models of fungal infection; 3) To define the mechanisms of interaction of radiolabeled antibodies with the host immune system. The research proposed here will elucidate the fundamentals of the interactions between microorganisms, antibodies, particulate-emitting radioisotopes and the host immune system. Such knowledge will contribute to development of a novel therapeutic modality based on radioimmunotherapy for treatment of currently incurable or multidrug-resistant AIDS-associated opportunistic infections.
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