PRECLINICAL ANIMAL MODEL TO ASSESS THE SAFETY OF RETROVIRALLY RESISTANT CELLS

向HIV感染者施用逆转录病毒抗性细胞 正在积极研究中。 使用获得性免疫缺陷的小鼠模型 通过逆转录病毒诱导，我们探讨了安全性和有效性 逆转录病毒抗性细胞在易感宿主动物中。 两个不同 构建了同种异体小鼠品系，其中一个亲本品系 对鼠逆转录病毒敏感，另一个耐药。 重要的是，逆转录病毒耐药机制在两个耐药 菌株伙伴不同。 个体动物的嵌合体是 通过流式细胞术技术进行评估， 用逆转录病毒混合物接种。 对动物进行时间评估 淋巴结病，死亡时间，流式细胞术参数的变化， 以及逆转录病毒种类的回收。 尽管存在差异， 逆转录病毒耐药机制，存在大量，但较少 比大多数的抗性细胞没有提供保护 动物发展成淋巴结病， 与完全易感对照小鼠相同的时间范围或更快， 逆转录病毒种类的回收率相当。 然而，在多个 主要淋巴细胞群为耐药的动物 基因型，动物没有发展疾病，并有一个明显的 逆转录病毒水平降低。 重要的是，易感者的命运 细胞的抗病机制不同， 在一个敏感的淋巴细胞室显着减少， 组合，但另一个没有变化。 因此，很明显， 是敏感和抵抗淋巴细胞之间的关键平衡 决定动物是否死于疾病， 长期耐药，耐药机制可能决定了 易感细胞群体的命运。 该模型还解决了 与感染性逆转录病毒的嗜性变化有关的问题， 内源性逆转录病毒，存在于供体细胞的基因组中。 已计划进行其他研究，以确定关键耐药 细胞群负责提供保护， 疾病，以测试其安全性时，注入到逆转录病毒感染 动物，并用于评估病毒嗜性的变化。 Sechler，JMG，Lawler，A.，Hartley，JW，莫尔斯，HC，III和Rosenberg，AS. 在易感品系产生的异基因小鼠中诱导MAIDS 和抵抗疾病。 准备中的Mandarin。

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.