Targeting the oral cavity epithelium for inducing mucosal immunity against HIV

描述（由申请人提供）：2008年，由于艾滋病毒通过母乳从母亲传染给孩子，大约有70,000名新生儿感染了人类免疫缺陷病毒（HIV）。我们的目标是在唾液中诱导艾滋病毒中和抗体，使母乳中的艾滋病毒中和，防止艾滋病毒从母亲传染给孩子。为了实现这一目标，我们将利用口腔（OC）的天然免疫能力。OC天生具有许多淋巴组织，如扁桃体和粘膜组织中的树突状细胞（dc）。树突状细胞是一种有效的抗原呈递细胞，可以通过处理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中有一个富含DC的区，位于OC粘膜上皮的上几百微米处。我们将设计和开发一种基于微针的疫苗接种方法，这种方法被称为微针（MNs），它可以以微精度在dc附近靶向疫苗。MNs最初是为通过皮肤进行无痛接种而开发的。我们假设MNs可以被优化，使疫苗能够快速有效地递送到口腔上皮，并能产生粘膜和全身反应。我们将开发疫苗包被的MNs，这样它们就可以在OC上皮富含dc的区域传递它们的包被。本应用的目的有两个方面：(1)表征和优化微针涂层，以实现高抗原稳定性和递送效率；(2)比较兔的OC和肌肉注射（IM）免疫途径，使用特征明确的HIV抗原，重点关注唾液和其他远端粘膜中的抗HIV抗体。我们将使用血清、唾液、直肠液体和阴道液体，通过测量针对HIV-1的抗原特异性抗体和中和抗体来比较全身和粘膜免疫反应。本研究的预期结果包括一种有效且微创地将疫苗递送至OC上皮的方法，以及了解OC局部、其他远处粘膜表面和系统隔室的体液粘膜免疫反应。这些结果有望通过提供局部HIV疫苗递送的OC免疫应答的基本新知识来推进OC疫苗接种领域。这一新知识也可能适用于口腔的其他免疫病理状况，如口腔癌和牙龈炎。

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.