MECHANISM OF THE H-2 EFFECT OF VIRAL LEUKEMOGENESIS

病毒性白血病的 H-2 效应机制

• 批准号: 3165218
• 负责人: FRANK LILLY
• 金额: $ 23.24万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 1995-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3165218
• 关键词: Friend virus; MHC class I antigen; antigen presentation; bone marrow transplantation; cellular immunity; cytotoxic T lymphocyte; erythroleukemia; genetic mapping; genetically modified animals; laboratory mouse; major histocompatibility complex; microorganism immunology; tissue /cell culture; tissue mosaicism; transfection; viral leukemogenesis; virus RNA; virus antigen

Resistance to pathogenic agents such as retroviruses may be genetic or acquired. We propose studies of the erythroleukemic disease of mice induced by the complex Friend strain (FV) of mouse leukemia virus (MuLV) in which both types of resistance can be observed and appear to depend in part on similar underlying immunologic mechanisms involving the major histocompatibility complex of the mouse, H-2. Our findings may serve as models for the study of analogous aspects of HIV disease. Mice of certain genotypes that differ in the D region of H-2 show markedly different levels of genetic susceptibility or resistance to FV, but the mechanism of this presumably immunologic effect has never been definitively demonstrated. In particular, we will study the mechanisms whereby H-2 haplotypes that confer resistance to FV in homozygous mice no longer do so in congenic heterozygotes. We propose studies of this effect that will precisely identify the D region genes involved by the use of genetic mapping with recombinant and mutant H-2 haplotypes, by the analysis of relevant strains of transfected cells and of transgenic mice and by studies based on the known properties of genes mapping in this region. We will also study aspects of the cellular immune response to FV that appear critical in the development of acquired resistance to the virus. We will identify specific amino acid sequences in the viral gag/pol and env genes that, together with H-2D region gene products, constitute the structures seen by FV-specific cytotoxic T lymphocytes (CTL). We will develop virus-related RNA constructs that are defective for replication and nonpathogenic but enriched for the determinants of the epitopes recognized by CTL that we will have identified. We will package these epitope-enriched constructs in FV particles which should then be able to generate a strong immune response in host mice both by stimulation of the class II H-22 gene-restricted pathway for antigen presentation and by stimulation of the class I H-22 gene-restricted endogenous pathway. The efficacy of these agents as candidate vaccines will be determined.

对病原体（例如逆转录病毒）的耐药性可能是遗传 或获得。 我们提出了小鼠红血病病的研究 由小鼠白血病病毒（MULV）的复杂朋友菌株（FV）诱导 在其中可以观察到两种类型的电阻并似乎依赖 部分涉及主要的基本免疫机制 小鼠的组织相容性复合物H-2。 我们的发现可能是 研究HIV疾病类似方面的模型。 在H-2区域不同的某些基因型的小鼠 显示出明显不同水平的遗传敏感性或对 FV，但是这种可能的免疫作用的机制从来没有 被明确证明了。 特别是，我们将研究 H-2单倍型赋予FV的H-2单倍型 纯合小鼠不再在异基因杂合子中这样做。 我们建议 该作用的研究将精确鉴定出D区域基因 通过使用重组和突变体H-2的遗传映射参与 单倍型，通过分析转染细胞的相关菌株和 基于基因的已知特性的转基因小鼠和研究 该区域的映射。 我们还将研究细胞的各个方面 对被收购的发展至关重要的对FV的免疫反应 对病毒的抗性。 我们将确定特定的氨基酸序列 在病毒性堵嘴/pol和env基因中，与H-2D区域基因一起 产品，构成FV特异性细胞毒性T所看到的结构 淋巴细胞（CTL）。 我们将开发与病毒相关的RNA构建体 复制和非病毒性有缺陷，但对 CTL认可的表位的决定因素我们将拥有 确定。 我们将在FV中打包这些富含表位的结构 然后应该能够产生强烈的免疫反应的颗粒 在宿主小鼠中，既通过刺激II类H-22基因限制的刺激 抗原表现和通过刺激I级H-22的途径 基因限制的内源途径。 这些代理商的功效 将确定候选疫苗。