REVERSAL OF T CELL DIFFERENTIATION DEFECTS IN AIDS

逆转艾滋病中的 T 细胞分化缺陷

• 批准号: 3546611
• 负责人: ELINOR M. LEVY
• 金额: $ 17.45万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-30 至 1989-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3546611
• 关键词: AIDS; T lymphocyte; antiAIDS agent; antiviral agents; autoradiography; cell population study; cellular pathology; colony stimulating factor; drug screening /evaluation; flow cytometry; helper T lymphocyte; human immunodeficiency virus 1; human subject; immune adherence reaction; immunofluorescence technique; immunopharmacology; interferons; interleukin 2; leukocyte activation /transformation; leukopoiesis; suppressor T lymphocyte; suramin; thymosin

The central defect in AIDS is a loss of T4 cells. Current treatment protocols have not been able to reverse this decline and as a result they do not enhance survival. We suggest the lack of an effective treatment is due to fact that the pathogenesis of AIDS following HTLV-III infection and in particular the mechanism for the massive loss of T cells is not clear. The decline in T4 cells is reflected in an increasing inability of cells from patients to form T cell colonies in agar (CFU-T). We propose to use this CFU-T assay to inverigate mechanisms for the loss of T cells and treatment strategies to reverse this loss. We have documented a significant decrease in CFU -T formation in lymphadenopathy (LAS)S patients which becomes more pronounced in AIDS. This is due in part to a lack of precursor cells, the presence of suppressor cells and suppressive factors. These defects can be partially reversed by the in vitro addition of certain modulators such as phosphonoformate and thymosin fraction 5, but not by others such as interleuklin-2 and interferon. We propose to continue investigations into the nature of the differentiation defect and its relation to the in vivo loss of T cells. We suggest the loss of a small number of infected T cells would not lead to the overall decline in T cell number without a concomitant block in differentiation which prevents their replacement. In particular we will investigate the role of HTLV-III and other viral co-factors in this process. We will further continue to test compounds for their ability to modulate colony formation. These in vitro tests will be carried out in parallel to in vivo clinical trials. It is possible that the in vitro assay can be used to predict which drug or combination of drugs will contribute to a reconstitution of T cell numbers in vivo, and identify those individuals most likely to benefit from a particular treatment.

AIDS中的中心缺陷是T4细胞的损失。 当前治疗 协议无法扭转这一下降，结果他们 不要提高生存。 我们建议缺乏有效的治疗方法是 由于事实是，HTLV-III感染后的艾滋病发病机理和 特别是，T细胞大规模丢失的机制尚不清楚。 T4细胞的下降反映在细胞的无能为力中 从患者中形成琼脂（CFU-T）中的T细胞菌落。 我们建议使用 该CFU-T分析以倒t细胞和T细胞的损失机制 扭转这一损失的治疗策略。 我们已经记录了CFU -T形成的显着减少 淋巴结肿大（LAS）的患者在艾滋病中变得更加明显。 这部分是由于缺乏前体细胞，存在 抑制细胞和抑制因素。 这些缺陷可以部分 体外添加某些调节剂，例如 磷酸构酸盐和胸腺素馏分5，但没有其他 Interleuklin-2和干扰素。 我们建议继续调查 分化缺陷的性质及其与体内的关系 T细胞的丧失。 我们建议损失少量感染的T细胞 没有A 差异化的伴随块阻止了它们的替代。 在 特别是我们将研究HTLV-III和其他病毒的作用 在此过程中的联合因素。 我们将进一步测试化合物的 他们调节菌落形成的能力。 这些体外测试将是 与体内临床试验并行进行。 有可能 体外测定可用于预测哪种药物或组合 药物将导致体内T细胞数的重构，并且 确定那些最有可能从特定的人受益的人 治疗。