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: 8116236
• 负责人: MICHELLE A LOWES
• 金额: $ 38.14万
• 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/8116236
• 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. PUBLIC HEALTH RELEVANCE: Dendritic cells (DCs) are a "choke point" in the evolution of skin lesions in psoriasis and other chronic inflammatory skin diseases. These DCs and their precursors represent a novel and more specific target for preventing and treating such chronic inflammation.

描述(由申请人提供)：在过去的10年里，牛皮癣的治疗取得了很大的进步，主要是使用T细胞靶向治疗。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一个更具吸引力的靶点。DC通过驱动致病的Th1/17细胞反应，在慢性炎症的进化中代表了一个“瓶颈”。我们以前曾解剖过银屑病的DC-T细胞轴，但现在有一个重要的机会来理解更多近端DC的作用和功能。我们的团队首先描述了一组“炎性”髓系树突状细胞，它们与银屑病皮损中的T细胞一样丰富。这些炎性树突状细胞在我们检查的每一种银屑病治疗中都会减少，但如果治疗没有清除银屑病，这些炎症DC就不会减少。在这一瓶颈抑制树突状细胞将使我们能够防止皮肤炎症病变的发展和削弱慢性炎症器官疾病，以及治疗现有的病变。我们的中心假设是，循环中的CD16+单核细胞被招募到皮肤中，被局部环境激活，发展为炎性树突状细胞。由于CX3CL1/Fractalkine的趋化梯度，这些单核细胞迁移到皮肤中，局部环境中可以激活单核细胞的抗菌肽是候选药物。在小鼠模型中，有许多单核细胞成为炎性DC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。尽管在人类中知之甚少，但循环CD16+单核细胞在银屑病和其他许多情况下都会升高，包括脓毒症、类风湿性关节炎、艾滋病毒感染和冠状动脉疾病。这项提议中的实验将直接增强我们对单核细胞群体及其产生的DC和巨噬细胞的知识，并支持开发针对牛皮癣和其他自身免疫性疾病中的这些细胞的新治疗方案。目前治疗具有关键致病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。如果树突状细胞可以被选择性地靶向，那么先天免疫系统就可以在保留适应性免疫系统的同时受到抑制。实际上，我们可以开发出通常不具有免疫抑制作用的抗炎疗法。这种DC选择性的方法可以带来更安全的结果，并显著降低感染和恶性肿瘤的风险。例如，有一些新的治疗方法专门减少了所提议的单核细胞DC前体。靶向CX3CR1的药物正在开发中，有望作为一种替代方法来抑制前体细胞向皮肤的迁移，从而防止拟议的致病DC的发展。这一信息将为预防银屑病皮损的启动和维持提供一种新的令人兴奋的和特异的治疗策略，这一新知识可以探索到其他皮肤病和自身免疫性疾病。 与公共卫生相关：树突状细胞(DC)是牛皮癣和其他慢性炎症性皮肤病皮损演变过程中的“瓶颈”。这些DC及其前体代表了预防和治疗这种慢性炎症的新的和更具体的靶点。