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

摘要： 银屑病是一种使人衰弱的自身免疫性疾病，影响着全球1.25亿人。虽然一些患者 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。我们实验室和其他人的研究表明，这些炎症T细胞反应 由树突状细胞（DCs）编程。皮肤DC系统是复杂的并且由不同的子集组成， 每一种都具有独特的受体，用于诱导免疫应答或免疫耐受。广泛理解 DC的类型和独特的信号，促进炎症T细胞反应的银屑病是一个差距， 仍然是为病人设计急需的救济所必需的。 本申请集中于我们最近在皮肤中发现的一种新的人DC亚群，其由CD 5 表情CD 5 + DC存在于健康人皮肤的表皮和真皮中，并且在免疫调节方面具有上级优势。 它们激活效应子和炎性TH细胞应答（包括CTL、TH 1、TH 17和TH 22）的能力。 此外，这些DC在银屑病炎症皮肤中明显更丰富，这表明它们是至关重要的 发病机制中的参与者与这一概念相一致，提供了新的初步数据来证明CD 5 其功能是触发DC成熟和炎性T细胞活化的炎性途径。CD 5缺陷型 DC在活化时产生较少的炎性细胞因子，并且活化T细胞的效率低于WT DC。 此外，CD 5-/-小鼠在银肩病小鼠模型中表现出减少的病理学。这些结果进一步要求 表达CD 5的树突状细胞对皮肤免疫功能的影响及其在银屑病治疗中的应用 疗法我们的中心假设是： CD 5代表了DC上的一种新的免疫刺激分子， CD 5 + DC的功能在自身免疫中起重要作用。 为了验证这一点，在目标1中，我们提出了实验来确定DC上的CD 5促进CD 5表达的机制。 目的2将确定CD 5是否驱动T细胞介导的免疫应答， 通过使用我们开发的缺乏DC上特异性CD 5的新小鼠，研究银屑病皮肤炎症;以及 在目的3中，我们将确定银屑病患者皮肤中CD 5 + DC的解剖分布，物理相互作用， 免疫细胞和自身反应性T细胞的激活。 预计这些研究将导致对CD 5-T细胞免疫调节的新的基本见解。 表达DC，并将对靶向和灭活DC的策略产生直接影响，导致安全和 有效应用于牛皮癣和皮肤内外的其它炎性疾病。

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.