PRECLINICAL ANIMAL MODEL TO ASSESS THE SAFETY OF RETROVIRALLY RESISTANT CELLS

评估逆转录病毒抗性细胞安全性的临床前动物模型

• 批准号: 5200785
• 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/5200785
• 关键词: Retroviridae; Retroviridae disease; cell population study; cell sorting; disease /disorder model; disease /disorder proneness /risk; drug adverse effect; genetic strain; immunity; laboratory mouse; liposomes; microorganism immunology; model design /development; tissue mosaicism

Administration of retrovirally resistant cells to HIV infected humans is under active study. Using a murine model of acquired immunodeficiency induced by retroviruses, we explored the safety and efficacy of retrovirally resistant cells in a susceptible host animal. Two different strains of allophenic mice were constructed, in which one parent strain was susceptible and the other resistant to murine retroviruses. Importantly, the mechanism of retroviral resistance in the two resistant strain partners differed. Lymphoid chimerism of individual animals was assessed by flow cytometric techniques and the animals subsequently inoculated with the retroviral mix. The animals were assessed for time to lymphadenopathy, time to death, changes in flow cytometric parameters, and for recovery of retroviral species. Despite differences in mechanism of retroviral resistance, the presence of substantial, but less than predominant numbers of resistant cells afforded no protection against disease, with animals developing lymphadenopathy and dying in the same time frame or more rapidly than fully susceptible control mice and with comparable recovery of retroviral species. However, in multiple animals in which the predominant lymphoid population was of the resistant genotype, the animals failed to develop disease, and there was a marked reduction in level of retrovirus. Importantly, the fate of susceptible cells differed depending on the mechanism of disease resistance, with a marked reduction in the susceptible lymphoid cell compartment in one combination but no change in the other. Thus, it is apparent 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, and that the mechanism of resistance may determine the fate of the susceptible cell population. This model also addresses issues pertaining to changes in tropism of the infective retrovirus and of endogenous retroviruses, present in the genome of donor cells. Additional studies have been planned to identify the critical resistant cellular populations responsible for conferring protection against disease, for testing their safety when infused into retrovirally infected animals, and for assessing changes in viral tropism. Sechler, JMG, Lawler, A., Hartley, JW, Morse, HC,III, and Rosenberg, AS. Induction of MAIDS in Allophenic Mice Generated from Strains Susceptible and Resistant to Disease. Manuscript in Preparation.

对感染艾滋病毒的人施用抗逆转录病毒细胞 正在积极研究中。 使用获得性免疫缺陷的小鼠模型 由逆转录病毒诱导，我们探索了其安全性和有效性 易感宿主动物中的逆转录病毒抗性细胞。 两种不同的 构建了同种异体小鼠品系，其中一个亲本品系 一个对鼠逆转录病毒敏感，另一个对鼠逆转录病毒有抵抗力。 重要的是，两种耐药病毒的逆转录病毒耐药机制 应变伙伴不同。 个体动物的淋巴嵌合状态 通过流式细胞术技术和随后的动物进行评估 接种逆转录病毒混合物。 对动物进行时间评估 淋巴结肿大、死亡时间、流式细胞术参数的变化、 以及逆转录病毒物种的恢复。 尽管存在差异 逆转录病毒耐药机制，大量存在，但较少 大部分耐药细胞无法提供保护 对抗疾病，动物出现淋巴结病并在体内死亡 与完全易感的对照小鼠相比，时间范围相同或更快，并且 逆转录病毒种类的回收率相当。 然而，在多个 主要淋巴群体具有耐药性的动物 基因型，动物没有发病，并且有显着的 逆转录病毒水平降低。 重要的是，易感者的命运 细胞根据抗病机制的不同而有所不同， 1. 易感淋巴细胞室显着减少 组合，但其他没有变化。 由此可见，有 是敏感淋巴细胞和耐药淋巴细胞之间的关键平衡 这决定了动物是否会死于疾病，或获得长久的生命 术语阻力，并且阻力机制可能决定 易感细胞群的命运。 该模型还解决了 与感染性逆转录病毒的趋向性变化有关的问题和 存在于供体细胞基因组中的内源性逆转录病毒。 已计划开展更多研究来确定关键耐药性 负责提供保护的细胞群 疾病，用于测试注入逆转录病毒感染者时的安全性 动物，并用于评估病毒向性的变化。 Sechler, JMG、Lawler, A.、Hartley, JW、Morse, HC,III 和 Rosenberg, AS。 易感品系产生的异种小鼠中 MAIDS 的诱导 和抗病能力。 手稿正在准备中。