Interaction of AIDS-associated microbes with radiation

描述（由申请人提供）：某些与艾滋病相关的无法治愈的机会性传染病的发生，加上细菌和真菌的多重耐药菌株的出现，迫切需要新的抗菌治疗方法。我们最近建议使用放射免疫疗法（RIT）作为治疗机会性感染的一种新方式，即使用放射性标记的特异性抗体向病原体传递杀微生物辐射。通过证明放射性标记抗体可用于实验性新型隐球菌感染的治疗，实现了这一策略的原理证明。本应用程序旨在研究在放射免疫治疗期间，艾滋病相关的机会微生物与特定抗体传递给微生物细胞的颗粒辐射之间的相互作用。我们的目标是开展基础研究，探索与抗菌放射免疫治疗相关的基本问题，以进一步发展这一有前途的实验性治疗。新形梭菌作为真菌艾滋病相关机会性感染放射免疫治疗的模型系统有几个优点，包括存在良好的动物模型和几种特性良好的免疫试剂的可用性。此外，单克隆抗体（mAb）疗法已经在临床试验中使用mAb 18B7治疗新生梭状菌。我们假设，放射性标记抗体将是有效的递送载体靶向辐射到微生物细胞。我们预计RIT将通过“直接命中”、“交叉射击”或“旁观者”效应杀死目标微生物。我们还假设，在没有对周围组织和主要器官造成临床显著辐射损伤的情况下，在不损害免疫系统成分的情况下，有可能在体内根除新生芽胞杆菌感染。本文提出了三个目标：1)研究放射性标记抗体与真菌细胞相互作用的放射生物学机制；2)建立真菌感染动物模型放射免疫治疗的药理学、疗效和毒性的相关性；3)明确放射性标记抗体与宿主免疫系统相互作用的机制。这里提出的研究将阐明微生物，抗体，微粒放射同位素与宿主免疫系统之间相互作用的基本原理。这些知识将有助于开发一种基于放射免疫疗法的新型治疗方式，用于治疗目前无法治愈或耐多药艾滋病相关的机会性感染。

DESCRIPTION (provided by applicant): 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 between AIDS-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-associated opportunistic infections which include the existence of 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.