Cutaneous Immunity and Vaccinia

该项目的首要目标是了解经皮接种猪瘟的机制。 人类皮肤感染牛痘(疤痕)会导致对天花的保护性免疫反应，并使用这种 帮助制定安全有效的疫苗接种策略的知识，特别是对患者 世卫组织目前不是接种对象(例如，特应性皮炎患者)。将进行研究 同时使用人类和小鼠模型系统。牛痘病毒对两个正常人群有效感染的可能性 以及特应性皮肤组织、细胞和人造皮肤结构，将通过Vanous技术进行评估。在……里面 与项目1的研究人员合作，将在不同的时间点采集皮肤和血液 来自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， 其中含有感染表皮病毒片段的朗格汉斯细胞迁移到引流淋巴 并分化为强大的成熟树突状细胞并激活NATve T细胞。这些T细胞扩增 克隆并分化为中枢记忆和皮肤归巢效应器记忆T细胞。效应器内存T 细胞从疫苗部位的真皮血管渗出，进入乳头状真皮和表皮。 中央记忆细胞进入次级淋巴组织，并提供长期免疫记忆。 我们将描述针对天花的保护性免疫反应的关键细胞和体液成分。 由于这些事件而产生的。我们将测试特应性皮炎患者和正常人的程度 接种MVA疫苗的志愿者在这种保护性反应中会产生类似的关键因素。在小鼠模型中， 我们将使用生物反应调节剂操纵皮肤微环境，并确定 这些动作是否提高了对牛痘的免疫反应。靶向转基因小鼠 影响树突状细胞迁移和功能的细胞因子和趋化因子在表皮中的表达 也有待研究。疫苗接种的效果将通过测试对牛痘挑战的抵抗力来评估 这些小鼠之前接种了MVA或牛痘疫苗，主要目标是加强疫苗接种。 效率。哈佛皮肤病研究中心研究了先天免疫和后天免疫 在皮肤中的反应机制超过15年。HSDRC的资源将为我们提供丰富的 为这些研究提供环境，并将加强与研究人员领导的项目的协作互动 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.