Cutaneous Immunity and Vaccinia

本项目的总体目标是了解经皮接种的机制， 带有牛痘的人皮肤（划痕）导致对天花的保护性免疫应答，并且使用这种免疫应答 帮助制定安全有效的疫苗接种策略的知识，特别是对患者 目前不是疫苗接种候选者的人（例如，特应性皮炎患者）。将进行研究 使用人和鼠模型系统。牛痘有效感染正常人和非正常人的潜力 和特应性皮肤组织、细胞和人造皮肤构造，将通过各种技术进行评估。在 与项目1的研究者合作，将在不同时间点采集皮肤和血液样本 接种疫苗的正常志愿者。我们将测试我们的皮肤免疫反应范例的有效性， 其中含有来自感染表皮的病毒片段的朗格汉斯细胞迁移到引流淋巴液 淋巴结并分化成有效的成熟树突状细胞并激活naTve T细胞。这些T细胞扩张 克隆并分化成中枢记忆和皮肤归巢效应记忆T细胞。效应记忆T 细胞从疫苗部位的真皮血管渗出并进入乳头状真皮和表皮。 中枢记忆细胞进入次级淋巴组织并提供长期免疫记忆。 我们将描述天花保护性免疫反应的关键细胞和体液成分 这些事件的结果。我们将测试特应性皮炎患者和正常人 接种MVA疫苗的志愿者产生这种保护性反应的类似关键要素。在小鼠模型中， 我们将用生物反应调节剂操纵皮肤微环境， 这些策略是否能提高对牛痘的免疫反应。转基因小鼠 影响树突状细胞迁移和功能的细胞因子和趋化因子的表皮表达将 也被研究。疫苗接种的效力将通过测试对牛痘攻击的抵抗力来评估， 这些小鼠在预先接种MVA或牛痘后，主要目的是增强疫苗接种 效率哈佛皮肤病研究中心研究了先天性和后天免疫 皮肤反应机制超过15年。HSDRC的资源将提供丰富的 这些研究的环境，并将加强与领导项目的研究人员的协作互动 1、2和4。

The overarching goal of this project is to understand the mechanisms by which transepidermal inoculation of human skin with vaccinia (scarification) leads to a protective immune response to smallpox, and to use this knowledge to help develop vaccination strategies that are both safe and effective, particularly for patients who currently are not vaccination candidates (e.g., patients with atopic dermatitis). Studies will be performed using both human and murine model systems. The potential for vaccinia to productively infect both normal and atopic skin tissue, cells, and artificial skin constructs, will be assessed by vanous techniques. In collaboration with investigators from Project 1, both skin and blood will be sampled at various time points from vaccinated normal volunteers. We will test the validity of our paradigm of cutaneous immune response, wherein Langerhans cells containing virus fragments from infected epidermis migrate to draining lymph nodes and differentiate into potent mature dendritic cells and activate naTve T cells. These T cells expand clonally and differentiate into central memory and skin-homing effector memory T cells. Effector memory T cells extravasate from dermal vessels at the vaccine site and enter the papillary dermis and epidermis. Central memory cells traffic into secondary lymphoid tissues and provide long-term immunolog ic memory. We will characterize key cellular and humoral elements of the protective immune response to variola generated as a result of these events. We will test the extent to which atopic dermatitis patients and normal volunteers vaccinated with MVA develop similar key elements of this protective response. In murine models, we will manipulate the cutaneous microenvironment with biological response modifiers and determine whether these maneuvers improve the immune response to vaccinia. Transgenlc mice with targeted epidermal expression of cytokines and chemokines that influence dendritic cell migration and function will also be studied. The efficacy of vaccination will be assessed by testing resistance to vaccinia challenge in these mice after prior vaccination with MVA or vaccinia, with a major goal being to enhance vaccination efficiency. The Harvard Skin Disease Research Center has studied both innate and acquired immune response mechanisms in skin for more than 15 years. The resources of the HSDRC will provide a rich environment for these studies and will enhance collaborative interactions with investigators leading projects 1, 2, and 4.