Interaction of AIDS-associated microbes with radiation

与艾滋病相关的某些无法治愈的机会性传染病的发生 耐多药细菌和真菌菌株的出现迫切需要新的方法来应对 抗菌治疗。我们最近建议使用放射免疫治疗(RIT)作为一种新的治疗方式 机会性感染的治疗，即使用放射性标记的特异性抗体来提供杀微生物性辐射 对病原体来说。这一策略的原理证明是通过证明放射性标记抗体可以 用于治疗实验性新生隐球菌感染。 这项申请建议调查艾滋病相关的机会微生物和 在放射免疫治疗期间，由特定抗体传递到微生物细胞的微粒辐射。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 进一步开发这一有希望的实验性治疗方法。新生链球菌作为一种模式有几个优点 真菌艾滋病相关机会性感染的放射免疫治疗系统 优秀的动物模型和几种特性良好的免疫试剂的可用性。此外， 利用单抗18B7对新生葡萄球菌进行的单抗治疗已经进入了临床试验阶段。我们 假设放射性标记抗体将是将辐射定向到微生物细胞的有效载体。我们 预计RIT将通过“直接命中”、“交叉火力”或“旁观者”效应杀死目标微生物。我们也 假设有可能在体内根除新生葡萄球菌感染，而不会对临床造成显著的辐射损伤 对周围组织和主要器官无损伤，对免疫系统各组成部分无损伤。三个目标是 建议： 1)探讨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)建立放射免疫治疗动物模型的药理、疗效和毒性之间的相关性。 真菌感染； 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、 释放微粒的放射性同位素和宿主免疫系统。这些知识将有助于发展一种 基于放射免疫疗法的治疗目前无法治愈或多药耐药的新疗法 艾滋病相关的机会性感染。

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.