Origin and Function of Inflammatory Dendritic Cells in Psoriasis.

描述（由申请人提供）：在过去的10年里，银屑病的治疗取得了很大的进展，主要是使用T细胞靶向治疗。然而，树突状细胞（dc）提供了一个更有吸引力的目标，以预防牛皮癣和其他自身炎症性疾病。dc通过驱动致病性Th1/17细胞反应，代表了慢性炎症进化的“瓶颈”。我们之前已经解剖了银屑病中的dc - t细胞轴，但现在有一个重要的机会来了解更多近端dc的作用和功能。我们的研究小组首先描述了一群“炎性”髓系dc，它们在牛皮癣皮肤病变中与T细胞一样丰富。这些炎性dc在我们所研究的银屑病的每次治疗中都会减少，但如果治疗没有清除银屑病，则不会减少。在这一瓶颈处抑制dc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性器官疾病，以及治疗现有病变。我们的中心假设是循环CD16+单核细胞被招募到皮肤中，被局部环境激活，发展成炎性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物质。在小鼠模型中有许多单核细胞变成炎性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。尽管在人类中所知甚少，循环CD16+单核细胞在牛皮癣和其他许多疾病中升高，包括败血症、风湿性关节炎、HIV感染和冠状动脉疾病。本提案中的实验将直接增强我们对单核细胞群体及其产生的dc和巨噬细胞的认识，并支持开发针对这些细胞的银屑病和其他免疫疾病的新治疗方案。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。如果可以选择性靶向dc，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，我们可以开发出抗炎治疗，而不是一般的免疫抑制。这种dc选择性方法可以带来更安全的结果，感染和恶性肿瘤的风险大大降低。例如，有新的治疗方法专门减少单核细胞DC前体。靶向CX3CR1的药物正在开发中，有望作为抑制前体细胞向皮肤迁移的替代方法，从而防止所提出的致癌性DC的发展。这一信息将为预防牛皮癣病变的发生和维持提供一种新的令人兴奋的特异性治疗策略，并且这一新知识可以在其他皮肤疾病和自身免疫性疾病中探索。

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.