Understanding the mechanism(s) of systemic antibody delivery, distribution, and localization to mucosal sites in the in vivo macaque model

了解体内猕猴模型中全身抗体递送、分布和粘膜部位定位的机制

• 批准号: 9756230
• 负责人: Ann M Carias
• 金额: $ 33.93万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-06 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756230
• 关键词: AIDS prevention; Anatomy; Animals; Anti-Retroviral Agents; Antibodies; Antibody Formation; Antibody-mediated protection; Area; Autoimmune Diseases; Award; Basic Science; Binding; Blood - brain barrier anatomy; Blood Circulation; Brain; Cells; Cessation of life; Clinical Trials; Data; Development; Drug or chemical Tissue Distribution; Epithelial Cells; Epithelium; Epitopes; Evaluation; Event; Explosion; Foundations; Future; Gene Expression; Generations; Grant; Growth and Development function; Gut Mucosa; HIV; HIV Infections; HIV vaccine; Human; Immunoglobulin Somatic Hypermutation; Immunoglobulin binding proteins; In Vitro; Infection; Infusion procedures; Injections; Intervention; Investments; Knowledge; Label; Light; Macaca; Macaca mulatta; Mentorship; Microscopy; Modeling; Modification; Monoclonal Antibodies; Movement; Mucous Membrane; Mutation; Organ; Passive Transfer of Immunity; Pathogenesis; Pathway interactions; Patients; Positron-Emission Tomography; Prevention; Primates; Protein Isoforms; Research; Research Personnel; SIV; Site; Squamous Epithelium; Stratum corneum; Systemic infection; Techniques; Therapeutic; Therapeutic Uses; Therapeutic antibodies; Time; Tissues; Vaccines; Vagina; Validation; Work; base; cancer therapy; career development; cell type; clinical application; cost; design; efficacy evaluation; imaging modality; in vivo; insight; interest; mucosal site; neutralizing antibody; nonhuman primate; novel; particle; prevent; rectal; simian human immunodeficiency virus; training opportunity; transmission process; two photon microscopy; vaccine development; vaginal mucosa

To date, although the number HIV-related deaths are on the decline due to antiretroviral and other biomedical interventions, there is still a vaccine lacking for HIV. Recently, there has been increased interest in the utilization of broadly neutralizing antibodies (bNAbs) as a vaccine strategy, which have been illustrated to bind and inactivate lentiviral particles in non-human primate models. Not only have bNAb passive transfer studies in rhesus macaques demonstrated protection against lentiviral infection, but have also led to the first bNAb human clinical trial, the Antibody Mediated Protection (AMP) study. Although these are valiant efforts towards blocking HIV infection, it is still unknown how these antibodies are delivered to mucosal sites where HIV transmission occurs. Gaining a better understanding of how these antibodies are anatomically distributed will have a great impact in the effort to develop a vaccine to prevent HIV acquisition. In order to accomplish this objective, I have been working to develop a novel platform to track fluorescently labeled antibodies in the in vivo rhesus macaque model. To date, utilizing this technique, I have revealed that antibodies take approximately one week to reach a steady state after infusion — an observation that could have implications for the ongoing AMP trial. Additionally, I have observed unique bNAb localization within tissue resident cells in those areas important in HIV transmission and pathogenesis, such as the rectal and vaginal mucosa, and brain. Based on these preliminary data, I propose in Aim 1 to identify the mechanisms of antibody transport and localization using the in vivo nonhuman primate model. In Aim 2, I will characterize the mechanism(s) of antibody association with specific, tissue resident cells at distinct anatomical sites after systemic application. Finally, in Aim 3, I will use the data from the first two aims to determine if antibody subclass influences tissue transport and localization. Overall, this award is integral to the completion of these aims in understanding the foundation of the mechanistic, basic science behind antibody distribution and localization events. With this opportunity, combined with the mentorship provided by Dr. Thomas Hope and Dr. Ronald Veazey, I can start to unravel the complexities of how protective antibodies are delivered to those sites involved in HIV transmission and pathogenesis. This knowledge is critical to advance the effort in the development of a vaccine that is able to provide protection from HIV infection, especially at mucosal sites. Additionally, the training opportunities to elucidate these mechanisms are extremely valuable to my development as a researcher, as it will also provide me with an important skillset and future experimentation that I can carry forward to academic independence.

迄今 干预措施，艾滋病毒仍然缺乏疫苗。最近，人们对 利用广泛中和抗体（BNAB）作为一种疫苗策略，已被说明以结合 并在非人类私有模型中灭活慢病毒颗粒。不仅有BNAB被动转移研究 恒河猕猴表现出对慢病毒感染的保护，但也导致了第一个BNAB 人类临床试验，抗体介导的保护（AMP）研究。尽管这些是为了努力 阻止艾滋病毒感染，仍然未知这些抗体如何递送到hiv的粘膜部位 发生传输。更好地了解这些抗体在解剖上分布的方式 在开发疫苗以防止艾滋病毒收购的努力中产生重大影响。为了实现这一目标 目的，我一直在努力开发一个新颖的平台，以跟踪IN中荧光标记的抗体 体内恒河猕猴模型。迄今为止，使用此技术，我透露抗体采用 输注后约一周才能达到稳态 - 这种观察可能具有影响 进行正在进行的放大器试验。此外，我观察到在组织居民细胞中的独特BNAB定位 这些区域在HIV传播和发病机理中很重要，例如直肠和阴道粘膜以及大脑。 基于这些初步数据，我在AIM 1中提出了确定抗体传输机制和 使用体内非人类私有模型进行本地化。在AIM 2中，我将表征 全身应用后，在不同解剖部位的特异性组织居民细胞的抗体关联。 最后，在AIM 3中，我将使用前两个目的的数据来确定抗体亚类是否影响组织 运输和本地化。总体而言，该奖项是完成这些目的不可或缺的一部分 抗体分布和定位事件背后的机械基础科学的基础。与此 机会，加上Thomas Hope博士和Ronald Veazey博士提供的指导职位，我可以开始 揭示如何将受保护抗体传递到涉及HIV传播的地点的复杂性 和发病机理。这些知识对于促进开发疫苗开发的努力至关重要 能够提供免受艾滋病毒感染的保护，尤其是在粘膜部位。此外，培训 阐明这些机制的机会对于我作为研究人员的发展非常有价值，因为 还将为我提供重要的技能和未来的实验 独立。