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

描述（由申请方提供）：拟定的研究将研究口腔粘膜免疫作为人类免疫缺陷病毒（HIV）疫苗的潜在给药途径。像大多数其他性传播疾病（STD）一样，HIV的主要感染部位是粘膜表面，并且像大多数其他STD一样，没有针对HIV的疫苗。拟议的实验将探索可能使用的口腔粘膜途径免疫艾滋病毒/性病通过诱导免疫在远端网站介导的共同粘膜免疫系统。我们将描述在2个口腔粘膜部位（颊窝和舌扁桃体上的粘膜下免疫）接种疫苗后，外周和粘膜（口腔、鼻腔、肺部、直肠和阴道）部位的先天性、适应性细胞和体液反应，并将其与肌内（IM）或皮内（ID）接种相同疫苗的反应进行比较。第一组实验在恒河猴中进行，将使用一种主要的HIV疫苗方案的SIV版本：DNA引发/复制缺陷的Ad 5疫苗加强。我们将把我们的观察扩展到使用许可的灭活流感疫苗（Fluzone）的人类。作为测试抗原。将在血液和粘膜部位测量适应性应答;将使用ELISpot和细胞内细胞因子染色测量抗原特异性T细胞，并将通过ELISA测量抗体。目的1将测试舌扁桃体上的粘膜下免疫是否在非人灵长类动物（NHP）和人类中产生稳健的外周B细胞和T细胞应答。这一目标将解决舌扁桃体免疫后的外周反应是否接近IM或ID免疫诱导的反应，并且是否大于颊窝粘膜下免疫后观察到的反应。将通过先天性免疫应答（全身树突状细胞表型和功能，以及血清细胞因子/趋化因子谱）研究不同途径引起的适应性应答差异的潜在机制。目的2将解决舌扁桃体免疫是否诱导粘膜细胞和体液反应在可测量的水平高于颊或IM/ID免疫。该目的将确定舌扁桃体途径引起的T细胞应答是否显示出更高的功能性和亲和力，以及该途径是否引起远端粘膜部位（直肠和宫颈/阴道）的应答。项目叙述：这些实验将提供关于口腔粘膜接种是否可以通过诱导由常见粘膜免疫系统介导的远端部位（如阴道和直肠）的免疫来提供针对性传播微生物的保护的数据。它还将研究这种免疫途径在需要鼻和肺免疫时对呼吸道病原体（如流感）的保护作用。

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.