PRECLINICAL ANIMAL MODEL TO ASSESS THE SAFETY OF RETROVI

用于评估 RETROVI 安全性的临床前动物模型

• 批准号: 6547391
• 负责人: A S ROSENBERG
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6547391
• 关键词: Retroviridae disease; cell population study; cell sorting; cell transplantation; cytotoxic T lymphocyte; disease /disorder model; disease /disorder proneness /risk; genetic strain; genotype; hematopoietic tissue transplantation; immune tolerance /unresponsiveness; immunity; laboratory mouse; microorganism immunology; model design /development; murine AIDSs; nonhuman therapy evaluation; tissue mosaicism

Transplantation of retrovirally resistant cells has been proposed as a therapeutic modality to treat HIV infected patients. We developed an animal model in which to explore the safety of administration of retrovirally resistant cells into susceptible animals. Using a murine model of acquired immunodeficiency induced by retroviruses, we established that there is a critical balance between susceptible and resistant lymphoid cells that determines whether the animals succumb to disease, or achieve long term resistance in that only animals containing >50% resistant cells were completely protected from disease. Critically, no changes in tropism of the infective retrovirus were detected during the course of the study . To assess the anti-retroviral mechanisms that confer resistance in this model, we have constructed animals in which the resistant cell population is deficient in receptors for IFN-gamma and are pursuing construction of resistant strain mice deficient in perforin, required for some aspects of cell mediated cytotoxicity. The latter mice have been infected and results pending. This program directly supports the mission of the Center by creating an animal model to allow us to anticipate the safety and potential efficacy of therapeutic modalities involving tranplantation of lymphoid populations resistant to HIV into HIV infected humans. One such protocol involving transplant of baboon bone marrow is already in progress.

逆转录病毒抗性细胞的移植已被提出作为一种治疗方法。 治疗HIV感染者的方法。 我们开发了一个 动物模型，以探讨给药的安全性 逆转录病毒抗性细胞植入易感动物体内。 使用鼠 逆转录病毒诱导的获得性免疫缺陷模型，我们 确定了易感和 抵抗淋巴细胞，决定动物是否屈服于 疾病，或实现长期抵抗，只有动物含有 >50%的抗性细胞被完全保护免于疾病。 重要的是， 感染性逆转录病毒的嗜性没有变化， 学习过程。 评估抗逆转录病毒机制， 在这个模型中赋予抗性，我们已经构建了动物， 抗性细胞群缺乏IFN-γ受体， 致力于构建穿孔素缺陷的抗性品系小鼠， 细胞介导的细胞毒性的某些方面所需的。 后一种老鼠 已被感染，结果待定。 该方案通过以下方式直接支持中心的使命： 创建 一个动物模型，让我们能够预测 涉及淋巴移植的治疗方式的功效 艾滋病病毒感染者的艾滋病病毒耐药人群。 一种这样的协议 包括狒狒骨髓移植已经在进行中。