Human Immune System Mouse Core

项目总结/摘要 人类免疫系统小鼠核心（Core H） 人类免疫系统小鼠核心（HISMC）将为HU CFAR研究人员提供人源化小鼠 研究人类免疫缺陷病毒（HIV）感染的模型。此外，HISMC将支持 早期的职业生涯胡CFAR调查人员通过一个可持续发展计划访问这些模型。 尽管对HIV感染者进行了广泛的相关研究，对外周血细胞和 组织活检，关于艾滋病毒发病机制和免疫的基本问题仍然没有答案。的能力 通过控制免疫系统的扰动来研究HIV在人类受试者中是有限的， 获得人体组织样本使得对艾滋病毒复制和人体免疫反应的研究， 艾滋病病毒很难在血液以外的地方传播。因此，研究人员转向动物模型，但 不幸的是，理想的HIV感染动物模型仍然是难以捉摸的。虽然猿类免疫缺陷 恒河猴的SIV感染提供了许多关于逆转录病毒的重要见解 发病机制和免疫，猕猴对SIV和人的免疫应答存在固有差异 对艾滋病毒的反应。此外，与NHP研究相关的费用限制了使用这种模式。解决 由于这些限制，已经产生了具有人免疫细胞的嵌合“人源化小鼠”。胡恒 HISMC生成互补的人源化小鼠模型：人外周血白细胞（hu-PBL） 小鼠、造血干细胞（hu-HSC）小鼠和骨髓-肝-胸腺（BLT）小鼠。研究支持 HISMC的研究表明，这些小鼠重现了人类HIV感染的多个方面， 例如阴道内激发后感染的“蚀相”的存在; 感染后外周血和粘膜组织中的CD 4 + T细胞;并支持先进的体内成像 HIV感染的多光子活体显微镜和生物发光成像。他们还提供了一个模型， 研究治疗的效果，如抗逆转录病毒疗法或抗体，对艾滋病毒。 在即将到来的资助期内，HISMC将提供这些人源化小鼠模型作为新的 MGH/合作伙伴医疗保健核心。因此，在小鼠的产生中涉及的所有成本及其 实验操作包括在服务价格中。CFAR支持将完全 针对代金券计划，以支持早期职业HU CFAR调查员获得这些 服务这些代金券将涵盖与人源化小鼠实验相关的费用，并将限于早期使用。 职业HU CFAR研究人员没有从其他来源获得人源化小鼠研究的资助。

PROJECT SUMMARY/ABSTRACT Human Immune System Mouse Core (Core H) The Human Immune System Mouse Core (HISMC) will provide HU CFAR investigators with humanized mouse models in which to study human immunodeficiency virus (HIV) infection. In addition, the HISMC will support early career HU CFAR investigators to access these models through a Voucher program. Despite extensive correlative studies of HIV-infected persons and ex vivo studies of peripheral blood cells and tissue biopsies, fundamental questions about HIV pathogenesis and immunity remain unanswered. The ability to study HIV through controlled perturbations of the immune system is limited in human subjects, and limited access to human tissue samples makes the investigation of HIV replication and human immune responses to HIV difficult in compartments other than the blood. Investigators have therefore turned to animal models, but unfortunately an ideal animal model of HIV infection has remained elusive. Although simian immunodeficiency virus (SIV) infection of rhesus macaques has provided many critically important insights into retroviral pathogenesis and immunity, there are differences inherent in macaque immune responses to SIV and human responses to HIV. Moreover, expenses associated with NHP studies limit access to this model. To address these limitations, chimeric “humanized mice” with human immune cells have been generated. The HU CFAR HISMC generates complementary humanized mouse models: human peripheral blood leukocytes (hu-PBL) mice, hematopoietic stem cells (hu-HSC) mice and bone marrow-liver-thymus (BLT) mice. Studies supported by the HISMC have demonstrated that these mice recapitulate multiple aspects of HIV infection in humans such as the presence of an “eclipse phase” of infection following intravaginal challenge; similar depletion of CD4+ T cell in peripheral blood and mucosal tissues following infection; and support advanced in vivo imaging of HIV infection by multiphoton-intravital microscopy and bioluminescence imaging. They also offer a model to study the effect of treatment, such as ART or antibodies, against HIV. In the coming funding period, the HISMC will provide access to these models of humanized mice as a new MGH/Partners Healthcare Core. As such, all costs involved in the generation of the mice and their experimental manipulations are included in the price of the services. The CFAR support will be entirely directed towards a voucher program to support access of early career HU CFAR investigators to these services. These vouchers will cover costs related to humanized mice experiments and will be restricted to early career HU CFAR investigators who have no grant funding for humanized mouse studies from other sources.