Immunization of Oral Mucosa for Induction of Rectal and Genital Mucosal Immunity

描述（由申请人提供）：拟议的研究将研究口腔黏膜免疫作为人类免疫缺陷病毒（HIV）疫苗递送的潜在途径。像大多数其他性传播疾病（std）一样，HIV的主要感染部位在粘膜表面，并且像大多数其他性传播疾病一样，HIV没有疫苗。本实验将探索口腔粘膜途径通过粘膜共同免疫系统介导的远端免疫诱导来免疫HIV/ std的可能性。我们将描述外周和粘膜（口腔、鼻腔、肺、直肠和阴道）对2个口腔粘膜部位（颊窝和舌扁桃体上的粘膜下免疫）接种疫苗的先天、适应性细胞和体液反应，并将其与肌肉注射（IM）或皮内注射（ID）对相同疫苗的反应进行比较。在恒河猴中进行的第一组实验将使用一种主要HIV疫苗方案的SIV版本：DNA引物/复制无能的Ad5疫苗增强。我们将把我们的观察扩展到使用许可的灭活流感疫苗（Fluzone）作为测试抗原的人类。将在血液和粘膜部位测量适应性反应；采用ELISA法检测抗原特异性T细胞，采用ELISA法检测细胞内细胞因子染色和抗体。目的1将测试舌扁桃体粘膜下免疫是否在非人灵长类动物和人类中产生强大的外周B细胞和t细胞反应。本研究旨在探讨舌扁桃体免疫后的外周反应是否与IM或ID免疫引起的外周反应相近，是否比颊窝粘膜下免疫引起的外周反应更大。不同途径引发的适应性反应差异的可能机制将通过先天免疫反应（全身树突状细胞表型和功能，血清细胞因子/趋化因子谱）的研究来研究。目的2将探讨舌扁桃体免疫是否诱导粘膜细胞和体液反应，其水平是否明显高于颊免疫或IM/ID免疫。该目的将确定舌扁桃体途径引起的t细胞反应是否具有更高的功能性和亲切性，以及该途径是否在远端粘膜部位（直肠和宫颈/阴道）引起反应。它还将调查在需要对鼻子和肺部进行免疫时，这种免疫途径对预防呼吸道病原体（如流感）的有用性。

DESCRIPTION (provided by applicant): The proposed research will investigate oral mucosal immunization as a potential route for delivery of human immunodeficiency virus (HIV) vaccines. Like most other sexually transmitted diseases (STDs), HIV's primary site of infection is at mucosal surfaces, and like most other STDs, there is no vaccine for HIV. The proposed experiments will explore the possible use of the oral mucosal route for immunization against HIV/STDs through induction of immunity at distal sites mediated via the common mucosal immune system. We will characterize innate, adaptive cellular, and humoral responses in the periphery and in mucosal (oral, nasal, pulmonary, rectal, and vaginal) sites to vaccines given at 2 oral mucosal sites (submucosal immunization in the buccal fossa and over the lingual tonsil) and compare them to responses to the same vaccines given intramuscularly (IM) or intradermally (ID). The first set of experiments, in rhesus macaques, will use an SIV version of one of the leading HIV vaccine regimens: DNA prime/replication-incompetent Ad5 vaccine boost. We will extend our observations to humans using a licensed inactivated influenza vaccine (Fluzone.) as a test antigen. Adaptive responses will be measured in the blood and at mucosal sites; antigen-specific T cells will be measured using ELISpot and intracellular cytokine staining and antibody will be measured by ELISA. Aim 1 will test whether submucosal immunization over the lingual tonsil produces robust peripheral B- and T-cell responses in both nonhuman primates (NHPs) and humans. This aim will address whether peripheral responses after lingual tonsil immunization approximate those induced by IM or ID immunization and are greater than those seen after submucosal immunization in the buccal fossa. Possible mechanisms underlying differences in adaptive responses elicited by different routes will be investigated via studies of innate immune responses (systemic dendritic cell phenotype and function, and serum cytokine/chemokine profiles). Aim 2 will address whether lingual tonsil immunization induces mucosal cellular and humoral responses at measurably higher levels than buccal or IM/ID immunization. This aim will determine whether T-cell responses elicited by the lingual tonsil route show higher functionality and avidity, and if this route elicits responses in distal mucosal sites (rectum and cervix/vagina). Project Narrative: These experiments will provide data on whether vaccination of the oral mucosa can provide protection against sexually transmitted organisms, through induction of immunity at distal sites (such as the vaginal and rectum) mediated by the common mucosal immune system. It will also investigate the usefulness of this route of immunization for protection against respiratory pathogens, such as influenza, when immunity in the nose and lungs is desired.