Targeting the oral cavity epithelium for inducing mucosal immunity against HIV

描述（由申请人提供）：2008年，约有70，000名新生儿感染了人类免疫缺陷病毒（HIV），原因是HIV通过母乳从母亲传播给婴儿。我们的目标是在唾液中诱导艾滋病毒中和抗体，使牛奶中的艾滋病毒中和，防止艾滋病毒母婴传播。为了实现这一目标，我们将利用口腔（OC）的天然免疫活性。OC天然具有许多淋巴组织，如扁桃体，并且在粘膜组织中具有树突状细胞（DC）。DC是有效的抗原呈递细胞，其可以通过加工抗原并将其呈递给驻留在淋巴组织中的T细胞来帮助诱导强粘膜免疫。在OC中，存在DC富集区，其位于OC粘膜上皮的上几百微米中。我们将设计和开发一种基于称为微针（MN）的显微针的疫苗接种方法，该方法可以以微精度将疫苗靶向靠近DC。MN最初被开发用于通过皮肤进行无痛疫苗接种。我们假设，MN可以优化，使快速和有效地将疫苗输送到口腔上皮，并可以产生粘膜和全身反应。我们将开发疫苗包被的MN，使得它们可以在OC上皮的富含DC的区域中提供它们的涂层。本申请的目的有两个：（i）表征和优化微针涂层，以实现高抗原稳定性和递送效率，以及（ii）使用充分表征的HIV抗原，重点关注唾液和其他远端粘膜中的抗HIV抗体，比较兔中OC和肌内（IM）免疫途径。我们将使用血清、唾液、直肠液和阴道液，通过测量抗HIV-1的抗原特异性抗体和中和抗体，比较全身和粘膜免疫应答。这项研究的预期结果包括一种有效和微创的方法，将疫苗输送到OC上皮细胞，并了解OC局部，其他远端粘膜表面和全身腔室的体液粘膜免疫反应。这些结果预计将通过提供当地HIV疫苗接种的OC免疫应答的基本新知识来推进OC疫苗接种领域。新的知识也可能适用于口腔的其他免疫病理条件，如口腔癌和牙龈炎。 公共卫生相关性：该项目旨在开发一种新的方法，将艾滋病毒疫苗输送到OC，并在唾液中诱导中和抗体，以阻止艾滋病毒从母亲传播给儿童。所述递送方法将广泛应用于口腔的其它局部疾病，例如牙周病和牙龈疾病。

DESCRIPTION (provided by applicant): In 2008, about 70,000 new infants were infected with human immunodeficiency virus (HIV) due to transmission of HIV from mother to child through the breast milk. Our goal is to induce HIV-neutralizing antibodies in the saliva to enable neutralization of HIV in the milk and prevent HIV transmission from mother to child. To achieve this goal we will exploit the natural immunocompetence of the oral cavity (OC). The OC is naturally endowed with many lymphoid tissues, such as tonsils, and with dendritic cells (DCs) in the mucosal tissue. DCs are potent antigen presenting cells that can help induce strong mucosal immunity by processing the antigen and presenting it to T-cells resident in the lymphoid tissues. In the OC there is a DC- rich zone, which is located in the upper few hundred micrometers of the OC mucosal epithelia. We will engineer and develop a vaccination approach based on microscopic needles called microneedles (MNs) that can target vaccines in close proximity to the DCs with microprecision. MNs were originally developed for painless vaccination through the skin. We postulate that MNs can be optimized to enable rapid and efficient delivery of vaccines to the oral epithelium and can generate mucosal and systemic responses. We will develop vaccine-coated MNs such that they can deliver their coatings in the DC-rich region of the OC epithelium. The objectives of this application are two fold: (i) to characterize and optimize microneedle coatings to achieve high antigen stability and delivery efficiency and (ii) to compare OC and intramuscular (IM) routes of immunization in rabbits using well characterized HIV antigens with focus on anti-HIV antibodies in the saliva, and at other distal mucosa. We will use serum, saliva, rectal fluids and vaginal fluids to compare systemic and mucosal immune responses through measurement of antigen specific antibodies and neutralizing antibodies against HIV-1. The outcomes expected from this research include a method for efficient and minimally invasive delivery of vaccines to OC epithelium, and an understanding of humoral mucosal immune response locally in the OC, at other distant mucosal surfaces and in the systemic compartment. These results are anticipated to advance the field of OC vaccination by providing fundamental new knowledge of OC immune responses from local HIV vaccine delivery. The new knowledge may also be applicable to other immuno-pathological conditions of the mouth such as oral cancer and gingivitis. PUBLIC HEALTH RELEVANCE: This project seeks to develop a novel methodology to deliver HIV vaccines to the OC and induce neutralizing antibodies in the saliva with the goal of stopping transmission of HIV from mother to child. The delivery methodology will have broad application with respect to other local diseases of the mouth such as periodontal and gum diseases.