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: 2569000
• 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/2569000
• 关键词: Retroviridae; Retroviridae disease; cell population study; cell sorting; cytotoxic T lymphocyte; disease /disorder model; disease /disorder proneness /risk; genetic strain; genotype; immune tolerance /unresponsiveness; immunity; laboratory mouse; microorganism immunology; model design /development; murine AIDSs; tissue mosaicism

Of many strategies to revitalize the immune system in HIV infected individuals, the transplant of lymphoid cells resistant to retroviral disease into afflicted individuals is being pursued, in the hope that such cells will mediate anti-retroviral immunity and restore immune responsiveness. However, little is known about qualitative or quantitative factors essential for mediation of resistance. Using a murine model of acquired immunodeficiency induced by retroviruses, we are exploring such parameters by constructing allophenic mice in which one parent is susceptible to MAIDS (murine acquired immunodeficiency syndrome) while the other is resistant. In two different strain combinations in which resistance was predicated on different mechanisms, the presence of substantial, but less than predominant numbers of resistant cells afforded no protection against disease, with such 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 the level of retroviral species diminished or disappeared. It is thus 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. We are now assessing what elements of anti-viral immunity are critical for protection in this model. We are constructing allophenic mice in which the resistant strain cells are deficient in interferon gamma, to assess whether this factor is critical for protection and will attempt to construct animals in which the resistant strain cells are deficient in perforin, to assess the role of CTL in this model. 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.

在许多恢复艾滋病毒感染者免疫系统的策略中， 个体，抗逆转录病毒的淋巴细胞的移植 人们正在寻求将疾病转移到患病个体身上，希望 这些细胞将介导抗逆转录病毒免疫， 响应能力。 然而，很少有人知道定性或 对调解耐药性至关重要的数量因素。 使用 逆转录病毒诱导的获得性免疫缺陷小鼠模型，我们 通过构建异基因小鼠来探索这些参数， 父母易患MAIDS（鼠获得性免疫缺陷 一种是综合征，另一种是耐药。 两种不同的菌株 根据不同的机制预测抗性的组合， 存在大量但不占主导地位的 抗性细胞不能提供抵抗疾病的保护， 出现淋巴结病并在同一时间段或更长时间内死亡 比完全易感的对照小鼠更快，恢复情况相当 逆转录病毒的种类。 然而，在多种动物中， 主要的淋巴细胞群体是耐药基因型， 动物没有发病，逆转录病毒种类的水平 减少或消失。 因此，很明显， 敏感和抵抗淋巴细胞之间的平衡决定了 动物是死于疾病还是获得长期抵抗力。 我们现在正在评估抗病毒免疫的哪些要素是至关重要的 在这种模式下的保护。 我们正在构建同种异体小鼠， 所述抗性菌株细胞缺乏干扰素γ， 评估此因素是否对保护至关重要，并将尝试 构建缺乏抗性品系细胞的动物 在穿孔素中，以评估CTL在该模型中的作用。 Sechler，JMG， Lawler，A.，Hartley，JW，莫尔斯，HC，III和Rosenberg，AS.诱导 耐药株和敏感株异基因小鼠的MAIDS研究 疾病。