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在体内系统中理解HTLV-1的免疫和神经发病机制的探索。这是由于HTLV-1包膜与鼠细胞的低效融合。最近，已经开发了一种嵌合HTLV-1病毒，其利用了Moloney-鼠白血病病毒的包膜基因，从而允许嵌合病毒与鼠细胞融合。利用这种嵌合病毒，我们最近证明了DC的消耗增强了CD 11 c-DTR转基因小鼠对HTLV-1的无细胞感染的易感性（Rahman等人，J. Immunol，出版中）。这些小鼠被独特地设计为选择性地消耗体内DC。与猿和人类细胞不同，鼠细胞通常对白喉毒素（DT）具有折射性。在CD 11 c-DTR-Tg小鼠中，DTR转基因与CD 11 c启动子（主要在鼠脾DC中表达）的融合允许在DT存在下完全消融DC，而不影响其他APC如B细胞和巨噬细胞。该系统已用于研究DC在几种病毒（包括LCMV、HSV-1和最近的HTLV-1）的发病机制中的作用（Rahman等人，免疫学杂志，印刷中）。然而，由于小鼠MHC背景，这些小鼠在研究人MHC I类相关免疫应答（例如在HAM/TSP患者中观察到的那些）中仍然存在问题。这个问题已经在一个单独的小鼠品系中得到解决，称为HHD II系，其表达人HLA-A2.1分子，并且敲除小鼠H-2Db MHC I类分子和β 2-微球蛋白，从而仅携带人HLA I类分子。我们先前已经证明了在这些小鼠中Tax 11-19特异性CTL应答的免疫和诱导（Manuel等人，勒克。生物学：2009年）。本文提出的研究试图产生一种新的转基因小鼠品系（HHD II/DTR-Tg），以研究在DC存在和不存在的情况下HTLV-1感染和随后的HLA-A2限制的细胞免疫应答。新产生的菌株可进一步用于研究HTLV-1介导的免疫发病过程中DC：T细胞相互作用的机制方面。在体内选择性消融DC的能力为探索这种独特的细胞群在各种感染和疾病模型中的作用提供了有力的工具。一个新的杂交株（HHD II/DTR-Tg）的发展，这里提出，将大大促进未来的研究HTLV-1免疫/神经发病机制，除了提供一个有价值的工具，科学界一般。 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细胞反应在复杂的自身免疫性/神经炎症性疾病，如HAM/TSP和多发性硬化症的重要信息。此外，这些研究的结果将揭示慢性病毒感染期间免疫细胞相互作用的动力学，如HTLV-1，HIV-1，肝炎病毒和单纯疱疹病毒。