Targeting the oral cavity epithelium for inducing mucosal immunity against HIV

描述(申请人提供)：2008年，约有70,000名新生婴儿感染人类免疫缺陷病毒(HIV)，原因是艾滋病毒通过母乳传播给母亲。我们的目标是诱导唾液中的艾滋病毒中和抗体，使牛奶中的艾滋病毒能够中和，并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)的自然免疫活性。OC自然具有许多淋巴组织，如扁桃体和粘膜组织中的树突状细胞(DC)。DC是一种强大的抗原提呈细胞，通过处理抗原并将其提呈给驻留在淋巴组织中的T细胞，可以帮助诱导强大的粘膜免疫。在OC中有一个富含DC的区域，位于OC粘膜上皮的上方几百微米处。我们将设计和开发一种基于被称为微针(MN)的微针的疫苗接种方法，这种方法可以以微精度针对接近DC的疫苗。MN最初是为通过皮肤接种无痛疫苗而开发的。我们推测，MNS可以被优化，以使疫苗能够快速有效地输送到口腔上皮细胞，并能够产生粘膜和全身反应。我们将开发疫苗包被的MN，使其能够在OC上皮富含DC的区域输送涂层。这项应用的目标有两个：(I)表征和优化微针涂层，以实现高抗原稳定性和递送效率；(Ii)比较OC和肌肉注射(IM)免疫兔的方法，使用特征良好的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、直肠液和阴道液来比较全身和粘膜免疫反应，方法是检测针对HIV-1的抗原特异性抗体和中和抗体。这项研究的预期结果包括一种有效和微创地将疫苗输送到OC上皮的方法，以及了解OC中局部的体液粘膜免疫反应，以及在其他远距离粘膜表面和全身隔室中的体液免疫反应。这些结果有望通过提供有关本地HIV疫苗接种的OC免疫反应的基本新知识，推动OC疫苗接种领域的发展。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。 公共卫生相关性：该项目寻求开发一种新的方法，向OC提供艾滋病毒疫苗，并在唾液中诱导中和抗体，目的是阻止艾滋病毒从母亲传给孩子。该给药方法将广泛应用于其他口腔局部疾病，如牙周病和牙周病。

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.