Origin and Function of Inflammatory Dendritic Cells in Psoriasis.

银屑病炎症树突状细胞的起源和功能。

• 批准号: 8510576
• 负责人: MICHELLE A LOWES
• 金额: $ 36.23万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510576
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Archives; Atherosclerosis; Autoimmune Diseases; Automobile Driving; Blood Component Removal; CD14 gene; CX3CL1 gene; CX3CR1 gene; Cells; Cellular Structures; Choking; Chronic; Clinical Trials; Colitis; Coronary Arteriosclerosis; Cutaneous; Data; Defensins; Dendritic Cells; Development; Disease; Dose; Environment; Evolution; FCGR3B gene; Fractalkine; Frequencies; Generations; Genetic Polymorphism; Genotype; Glucocorticoids; HIV Infections; Human; ITGAX gene; Image; Immune system; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Japan; Knowledge; Label; Lead; Lesion; Maintenance; Malignant Neoplasms; Modeling; Mus; Myelogenous; Myocarditis; Organ; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Population; Positioning Attribute; Production; Psoriasis; Recruitment Activity; Rheumatoid Arthritis; Risk; Role; Sepsis; Skin; T-Lymphocyte; TNFSF10 gene; Techniques; Therapeutic; Therapeutic immunosuppression; Translational Research; Treatment Protocols; University Hospitals; Work; antimicrobial; antimicrobial peptide; experience; healthy volunteer; in vivo; interleukin-23; keratinocyte; macrophage; migration; monocyte; mouse model; novel; precursor cell; prevent; research study; response; skin disorder; skin lesion; trafficking

DESCRIPTION (provided by applicant): Great progress has been made treating psoriasis over the last 10 years, predominantly using T cell-targeted therapies. However, dendritic cells (DCs) offer an even more attractive target to prevent psoriasis and other auto-inflammatory diseases. DCs represent a "choke point" in the evolution chronic inflammation by driving pathogenic Th1/17 cell responses. We have previously dissected the DC-T-cell axis in psoriasis, but now there is a significant opportunity to understand the role and function of more proximal DCs. Our group first described a population of "Inflammatory" myeloid DCs, which are as abundant as T cells in psoriasis skin lesions. These inflammatory DCs are reduced with every treatment for psoriasis we have examined, but not decreased if the treatment did not clear the psoriasis. Inhibiting DCs at this bottleneck will enable us to prevent inflammatory lesion development in the skin and debilitating chronic inflammatory organ diseases, as well as treat existing lesions. Our central hypothesis is that circulating CD16+ monocytes are recruited into skin, becoming activated by the local environment to develop into inflammatory DCs. These monocytes migrate into the skin due to the chemotactic gradient of CX3CL1/fractalkine, and anti-microbial peptides are candidates in the local environment that can activate the monocytes. There are many examples of monocytes becoming inflammatory DCs and macrophages in murine models, including colitis, infections, atherosclerosis, and myocarditis. Although much less in known in humans, circulating CD16+ monocytes are elevated in psoriasis and other many other conditions, including sepsis, rheumatoid arthritis, HIV infection, and coronary artery disease. The experiments in this proposal will directly enhance our knowledge of monocyte populations and the DCs and macrophages they give rise to, and support the development of new treatment protocols that target these cells in psoriasis and other autommmune diseases. The current approach to treating skin diseases with a critical pathogenic T cell component, is to use broad T cell-targeted immunosuppressive therapies. If DCs could be selectively targeted, the innate immune system could be repressed while the adaptive immune system was preserved. In effect, we could develop anti-inflammatory treatments that were not generally immunosuppressive. This DC-selective approach could lead to much safer outcomes, with considerably lower risk of infection and malignancy. For example, there are new treatments that specifically decrease the proposed monocytic DC precursors. Agents that target CX3CR1 are being developed, and are promising as an alternative approach to inhibit migration of the precursor cells into the skin, and hence prevent the development of the proposed causative DC. This information will provide a novel exciting and specific therapeutic strategy to prevent initiation and maintenance of psoriasis lesions, and this new knowledge could be explored in other skin diseases and autoimmune diseases.

描述（由申请人提供）：过去 10 年，主要使用 T 细胞靶向疗法，治疗牛皮癣取得了巨大进展。然而，树突状细胞（DC）为预防牛皮癣和其他自身炎症性疾病提供了更具吸引力的靶点。 DC 通过驱动致病性 Th1/17 细胞反应，成为慢性炎症进化过程中的“瓶颈”。我们之前已经剖析了银屑病中的 DC-T 细胞轴，但现在有一个重要的机会来了解更近端 DC 的作用和功能。我们的研究小组首先描述了一群“炎症性”骨髓 DC，其数量与牛皮癣皮损中的 T 细胞一样丰富。我们检查过的每一种银屑病治疗方法都会减少这些炎性树突状细胞，但如果治疗不能清除银屑病，这些炎症树突状细胞就不会减少。在这个瓶颈处抑制树突状细胞将使我们能够预防皮肤炎症病变的发展和使人衰弱的慢性炎症器官疾病，并治疗现有的病变。我们的中心假设是，循环 CD16+ 单核细胞被募集到皮肤中，被局部环境激活，发育成炎症 DC。由于 CX3CL1/fractalkine 的趋化梯度，这些单核细胞迁移到皮肤中，而抗微生物肽是局部环境中可以激活单核细胞的候选肽。在小鼠模型中，有许多单核细胞变成炎性树突状细胞和巨噬细胞的例子，包括结肠炎、感染、动脉粥样硬化和心肌炎。尽管在人类中鲜为人知，但循环 CD16+ 单核细胞在牛皮癣和其他许多疾病（包括败血症、类风湿性关节炎、HIV 感染和冠状动脉疾病）中升高。该提案中的实验将直接增强我们对单核细胞群及其产生的树突状细胞和巨噬细胞的了解，并支持开发针对牛皮癣和其他自身免疫性疾病中这些细胞的新治疗方案。目前治疗具有关键致病性 T 细胞成分的皮肤病的方法是使用广泛的 T 细胞靶向免疫抑制疗法。如果可以选择性地靶向树突状细胞，则可以抑制先天免疫系统，同时保留适应性免疫系统。实际上，我们可以开发通常不抑制免疫的抗炎治疗方法。这种 DC 选择性方法可以带来更安全的结果，同时大大降低感染和恶性肿瘤的风险。例如，有一些新的治疗方法可以专门减少所提出的单核 DC 前体。正在开发针对 CX3CR1 的药物，并有望作为抑制前体细胞迁移到皮肤中的替代方法，从而防止所提出的致病 DC 的发展。这些信息将提供一种新颖且令人兴奋的具体治疗策略，以预防银屑病病变的发生和维持，并且可以在其他皮肤病和自身免疫性疾病中探索这一新知识。