Developing epicutaneous vaccine approaches for protective immunity

描述(由申请者提供)：预防传染病疫苗接种仍然是公共卫生的一个重要和具有成本效益的目标。典型的免疫策略包括通过肌肉注射递送减毒病原体或其产品，这种方法由于疫苗运输、分发、给药和安全处置的后勤限制而引入了一些并发症。相比之下，皮肤表观免疫(EPI)，包括通过皮肤表面应用的免疫原，提供了一种令人兴奋的替代疫苗接种策略。虽然人们对这种新方法有很大的热情，但人们对它在启动能够对病原体产生保护性免疫的长寿命细胞介导的记忆反应方面的有效性知之甚少。在这项建议中，我们将探索使用皮肤表面免疫来激发CDS T细胞反应，从而能够控制小鼠的各种病毒和细菌病原体。在目标1中，我们将测试各种Toll样受体(TLR)对EPI的影响，重点是皮肤外刺激是否能诱导能够控制病原体的长寿记忆T细胞。推动这一反应的能力也将在这里受到考验。在目标2中，我们重点关注当小鼠暴露于不同的TLR以及当IL-12与L干扰素失衡时，对病原体单核细胞增多性李斯特菌的反应发生根本改变的报道。我们将探索这可能如何限制对这种病原体的皮肤外接种。在目标3中，我们研究了紫外线照射对EPI的影响。紫外线照射，就像轻微的晒伤可能发生的那样，众所周知会抑制一些细胞免疫反应。我们将确定紫外线对皮肤接种途径有什么抑制作用，以及如何控制这种抑制作用。

DESCRIPTION (provided by applicant): Vaccination against infectious diseases remains an important and cost-effective goal for public health. Typical immunization strategies involve delivery of attenuated pathogens or their products via intramuscular injections an approach which introduces a number of complications due to logistic limitations in vaccine transportation, distribution, administration and safe disposal. In contrast, epicutaneous immunization (EPI), involving immunogens delivered via surface application on the skin, offers an exciting alternative vaccination strategy. While there is much enthusiasm for this novel approach, relatively little is known about its efficacy at priming long-lived cell-mediated memory responses capable of protective immunity to pathogens. In this proposal, we will explore the use of epicutaneous immunization to prime CDS T cell responses capable of controlling various viral and bacterial pathogens in mice. In Aim 1, we will test the impact of various Toll-like receptors (TLR) on EPI, with a special emphasis on whether epicutaneous priming induces long lived memory T cells, capable of controlling pathogens. The ability to boost this response will also be tested here. In Aim 2, we focus on reports that the response to the pathogen Listeria monocytogenes is radically altered when mice are exposed to different TLRs, and when there is an imbalance of IL-12 versus Type-l Interferons. We will explore how this might limit the use of epicutaneous vaccination for this pathogen. In Aim 3, we study the effects of UV irradiation on EPI. UV irradiation, as might occur with mild sunburn, is known to suppress some cellular immune responses. We will determine what inhibitory effect UV has on epicutaneous vaccination approaches, and how this can be controlled.