Harnessing Human Dendritic Cell Subsets in Skin for the Design of Novel Immunotherapies

摘要： 牛皮癣是一种使人衰弱的自身免疫性疾病，影响着全球1.25亿人。虽然有些病人 可以用现有的非特异性疗法成功治疗，迫切需要开发新的靶向治疗方法。 持久且无副作用的治疗方法。皮肤中分泌炎性细胞因子的T细胞 促进慢性病变。我们实验室和其他实验室的研究表明，这些炎性T细胞反应 由树突状细胞(DC)编程。皮肤DC系统是复杂的并且由不同的子集组成， 每个受体都有独特的受体，用于诱导免疫反应或免疫耐受。广博的理解 在银屑病患者DC的类型和促进炎症T细胞反应的独特信号中，存在一个缺口 仍然是为患者设计急需的救济方案所必需的。 这个应用程序主要关注我们最近在皮肤中发现的一个新的人类DC亚群，它由CD5描绘 表情。CD5树突状细胞在健康人皮肤的表皮和真皮中均有分布，且在 它们激活效应器和炎症TH细胞反应的能力(包括CTL、TH1、TH17和TH22)。 此外，这些DC在银屑病发炎的皮肤中明显更多，这表明它们是至关重要的。 在发病机制中的球员。与这一概念相一致，提供了新的初步数据来证明CD5 触发DC成熟和炎症T细胞激活的炎症途径的功能。CD5缺陷 DC在激活时产生的炎性细胞因子较少，并且激活T细胞的效率低于WT DC。 此外，在牛皮癣的小鼠模型中，CD5-/-小鼠表现出较少的病理改变。这些结果进一步要求 CD5表达的树突状细胞对皮肤免疫的影响及其治疗银屑病的潜力探讨 心理治疗。我们的中心假设是： CD5是树突状细胞上一种新的免疫刺激分子，其比例或 CD5树突状细胞的功能在自身免疫中起重要作用。 为了测试这一点，在目标1中，我们提出了实验来确定DC上CD5促进的机制 激活和抗原摄取启动T细胞免疫；Aim 2将确定CD5是否驱动T细胞介导的 使用我们开发的一种新的小鼠，这种小鼠缺乏树突状细胞上的CD5，从而导致银屑病皮肤发炎； 在目标3中，我们将定义CD5树突状细胞在银屑病患者皮肤中的解剖分布、物理相互作用 与免疫细胞和自身反应性T细胞的激活有关。 预计这些研究将导致对CD5-免疫调节的新的基础性见解- 表达DC，并将直接影响针对DC和停用DC的战略，导致安全和 有效地应用于牛皮癣和其他皮肤内外的炎症性疾病。

ABSTRACT: Psoriasis is a debilitating auto-immune disease that affects 125 million people worldwide. While some patients can be treated successfully with existing non-specific therapies, there is a dire need for developing new targeted treatments that are durable and have on side effects. T cells in the skin that secrete inflammatory cytokines promote chronic lesions. Studies by our lab and others have shown that these inflammatory T cell responses are programmed by dendritic cells (DCs). The skin DC system is intricate and is comprised of distinct subsets, each with unique receptors for inducing either immune responses or immune tolerance. Extensive understanding of the type of DC and the unique signals that promote inflammatory T cell responses in psoriasis is a gap that remains and essential for designing much needed relief for patients. This application focuses on our recent discovery of a new human DC subset in skin that is delineated by CD5 expression. The CD5+ DC inhabit both the epidermis and the dermis of healthy human skin and are superior in their capacity to activate effectors and inflammatory TH cell responses (including CTLs, TH1, TH17 and TH22). Moreover, these DCs are significantly more plentiful in psoriatic inflamed skin, which suggests they are critical players in pathogenesis. Consistent with this notion, new preliminary data are provided to demonstrate that CD5 functions to trigger an inflammatory pathway of DC maturation and inflammatory T cell activation. CD5-deficient DCs produce less inflammatory cytokines upon activation, and activates T cells less efficiently than WT DCs. Moreover, CD5-/- mice display reduced pathology in a mouse model of psoriasis. These results mandate further investigation of the impact of CD5-expressing DCs on skin immunity and their potential exploration for psoriasis therapy. Our central hypothesis is that: CD5 represents a novel immune-stimulatory molecule on DCs, and that alterations to the proportions or functions of CD5+ DCs contribute significantly to autoimmunity. To test this, in Aim 1 we propose experiments to determine the mechanisms by which CD5 on DCs facilitates activation and antigen uptake to initiate T cell immunity; Aim 2 will determine whether CD5 drives T cell–mediated inflammation in psoriatic skin by using a new mouse that we developed that lack CD5 specifically on DCs; and in aim 3 we will define the anatomic distributions of CD5+ DCs in skin of psoriatic patients, physical interactions with immune cells and activation of autoreactive T cells. It is anticipated that these studies will lead to new fundamental insights into immune regulation by CD5- expressing DCs and will have direct impact on strategies to target and deactivate DCs, leading to safe and effective applications for psoriasis and other inflammatory diseases in and beyond the skin.