Modeling HTLV-1 infection and cellular immune response in HLA-A2-transgenic mice

HLA-A2 转基因小鼠的 HTLV-1 感染和细胞免疫反应建模

• 批准号: 8070131
• 负责人: ZAFAR K KHAN
• 金额: $ 19.28万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070131
• 关键词: Ablation; Address; Adult; Affect; Animal Model; Antigen-Presenting Cells; Antigens; Antiviral Agents; Ascaridil; Autoimmune Process; Autoimmunity; B-Lymphocytes; CD8B1 gene; Cell Communication; Cells; Chronic; Clinical; Communities; Complex; Cytotoxic T-Lymphocytes; Dendritic Cells; Development; Diphtheria Toxin; Disease; Disease model; Effectiveness; Elements; Epitopes; Frequencies; Future; Generations; Genes; HIV-1; HLA-A gene; HLA-A2 Antigen; HLA-A2.1; Hepatitis Viruses; Herpesvirus 1; Histocompatibility Antigens Class I; Human; Human T-lymphotropic virus 1; Hybrids; ITGAX gene; Immune; Immune response; Immunization; Immunodominant Epitopes; Individual; Infection; Investigation; Knockout Mice; Light; Lymphocytic choriomeningitis virus; MHC Class I Genes; Mediating; Mediator of activation protein; Modeling; Moloney Leukemia Virus; Mouse Strains; Multiple Sclerosis; Mus; Nature; Neuropathogenesis; Outcome; Pathogenesis; Patients; Play; Population; Predisposition; Process; Public Health; Retroviridae; Role; Route; Simplexvirus; Spinal Cord Diseases; Stimulus; Syndrome; System; T cell response; T-Cell Leukemia; T-Lymphocyte; Taxes; Transgenes; Transgenic Mice; Transgenic Organisms; Tropical Spastic Paraparesis; Viral; Virus; Virus Diseases; cell injury; design; diphtheria toxin receptor; human CREB1 protein; in vivo; insight; macrophage; neuropathology; pathogen; peripheral blood; promoter; response; tool

DESCRIPTION (provided by applicant): To date, the lack of a suitable small animal model has hindered our quest to understand the immuno- and neuropathogenesis of HTLV-1 in an in vivo system. This is due to the inefficient fusion of HTLV-1 envelope with murine cells. Recently, a chimeric HTLV-1 virus has been developed that utilizes the envelope gene of the Moloney-murine leukemia virus thereby allowing fusion of the chimeric virus with murine cells. Utilizing this chimeric virus we have recently demonstrated that depletion of DCs enhances susceptibility to cell-free infection of HTLV-1 in CD11c-DTR-transgenic mice (Rahman et al., J. Immunol, in press). These mice are uniquely designed to selectively deplete DCs in vivo. Murine cells, unlike simian and human cells, are generally refractive to diphtheria toxin (DT). The fusion of DTR transgene to the CD11c promoter (largely expressed in murine splenic DCs) in CD11c-DTR-Tg mice allows for the complete ablation of DCs in the presence of DT without affecting other APCs such as B cells and macrophages. This system has been used to study role of DCs in the pathogenesis of several viruses including LCMV, HSV-1, and recently HTLV-1 (Rahman et al., J. Immunol., in press). However, these mice still pose problem in studying human MHC class I-associated immune responses (such as those observed in HAM/TSP patients) due to the mouse MHC background. This issue has been addressed in a separate strain of mice, known as line HHD II, which express human HLA-A2.1 molecule and are knockout for the mouse H-2Db MHC class I molecule and beta2-microglobulin thereby carrying only human HLA class I molecules. We have previously demonstrated the immunization and induction of Tax 11-19-specific CTL response in these mice (Manuel et al., J. Leuk. Biol., 2009). The study proposed herein attempts to generate a new transgenic strain (HHD II/DTR-Tg) of mice to study HTLV-1 infection and subsequent HLA-A2-restrticted cellular immune response in the absence and presence of DCs. The newly generated strain could be further utilized to investigate mechanistic aspects of DC:T cell interaction during HTLV-1-mediated immunopathogenesis. The ability to selectively ablate DCs in vivo offers a powerful tool to explore the role of this unique cell population in various infection and disease models. The development of a new hybrid strain (HHD II/DTR-Tg), as proposed here, will greatly facilitate future studies of HTLV-1 immuno/neuropathogenesis in addition to providing a valuable tool to the scientific community in general. PUBLIC HEALTH RELEVANCE: The proposed studies are relevant to public health and will reveal significant information concerning the dendritic cells-regulated T cell responses during complex autoimmune/neuroinflammatory diseases such as HAM/TSP and multiple sclerosis. Additionally the results of these studies will shed light on the dynamics of immune cell interactions during chronic viral infections such as HTLV-1, HIV-1, hepatitis virus and herpes simplex virus.

描述（由申请人提供）：迄今为止，缺乏合适的小动物模型阻碍了我们的寻求了解HTLV-1在体内系统中的免疫发病和神经病的发生。这是由于HTLV-1包膜与鼠细胞的效率低下。最近，已经开发了一种嵌合HTLV-1病毒，该病毒利用了Moloney-Murine白血病病毒的包膜基因，从而允许将嵌合病毒与鼠细胞融合。利用这种嵌合病毒，我们最近证明，DC的耗竭增强了CD11C-DTR-转基因小鼠对HTLV-1无细胞无细胞感染的敏感性（Rahman等，J。Immunol，in Press）。这些小鼠是独特的设计，可在体内有选择地耗尽DC。鼠细胞与猿猴和人类细胞不同，通常对白喉毒素（DT）折射。 DTR转基因与CD11C启动子的融合（在鼠脾脏DC中很大程度上表达）在CD11C-DTR-TG小鼠中的融合可以在DT存在下完全消融DC，而不会影响其他APC（例如B细胞），例如B细胞和巨噬细胞。该系统已用于研究DC在包括LCMV，HSV-1和最近HTLV-1在内的多种病毒发病机理中的作用（Rahman等，J。Immunol。，印刷中）。但是，这些小鼠在研究人类MHC相关的免疫反应（例如在HAM/TSP患者中观察到的小鼠）仍然构成了问题。该问题已在单独的小鼠（称为HHD II系列）中解决，该菌株表达人HLA-A2.1分子，是小鼠H-2DB MHC I类分子和beta2-Microgloblobulin的敲除，因此仅携带人类HLA I类分子。以前，我们已经证明了这些小鼠的税收11-19特异性CTL反应的免疫和诱导（Manuel等，J。Leuk。Biol。，2009）。该研究提出的研究试图生成小鼠的新转基因菌株（HHD II/DTR-TG），以研究HTLV-1感染，并在不存在DC的情况下进行HLA-A2促进的细胞免疫反应。新生成的菌株可以进一步用于研究HTLV-1介导的免疫发病发生过程中DC：T细胞相互作用的机械方面。在体内有选择性消融DC的能力为探索这种独特的细胞种群在各种感染和疾病模型中的作用提供了强大的工具。如这里提出的那样，新的混合菌株（HHD II/DTR-TG）的开发将极大地促进对HTLV-1免疫/神经发病的未来研究，除了为总体上为科学界提供有价值的工具。 公共卫生相关性：拟议的研究与公共卫生有关，并将揭示有关树突状细胞调节的T细胞反应的重要信息，这在复杂的自身免疫性/神经炎症性疾病（例如HAM/TSP和多重硬化症）中。此外，这些研究的结果将阐明在慢性病毒感染（例如HTLV-1，HIV-1，HIV-1，乙型肝炎病毒和单纯疱疹病毒）期间免疫细胞相互作用的动力学。