Regulation of Cutaneous Accessory Cell Activity in Health and Disease

健康和疾病中皮肤辅助细胞活性的调节

• 批准号: 9344092
• 负责人: Mark Udey
• 金额: $ 7.77万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9344092
• 关键词: Antibodies; Antigen-Presenting Cells; Antigens; Attenuated; CD8B1 gene; Cell Differentiation process; Cell Ontogeny; Cell physiology; Cells; Collaborations; Contact hypersensitivity; Cutaneous; Cutaneous Leishmaniasis; Data; Defect; Dendritic Cells; Dermatology; Development; Disease; Epidermis; Follow-Up Studies; Goals; Hair follicle structure; Health; Homeostasis; Human; IgG1; Immune; Immune response; Immunization; Immunology; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-17; Interleukin-4; Journals; Laboratories; Langerhans cell; Leishmania; Leukocytes; Malignant Neoplasms; Manuscripts; Monoclonal Antibodies; Mouse Strains; Mus; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nature; Organ; Paper; Pathogenesis; Phenotype; Play; Process; Production; Proteins; Psoriasis; Publications; Publishing; Reaction; Recombinants; Regulation; Role; Signal Transduction; Skin; Syndrome; T-Lymphocyte; Testing; Th2 Cells; Time; Tokyo; Topical application; Transforming Growth Factor beta; Transgenic Mice; United States National Academy of Sciences; Universities; attenuation; base; chemokine; cytokine; gene gun; human disease; in vivo; insight; interest; keratinocyte; mouse model; neutralizing monoclonal antibodies; neutrophil; novel; overexpression; receptor; response; skin disorder; transcription factor; vaccine candidate; vaccine development

Our long standing interest in cutaneous dendritic cell physiology continues. Recently developed mice that are constitutively, or that can be made conditionally, Langerhans cell-deficient allow definitive studies of Langerhans cell function and development to be carried out. One of these strains of mice and a variety of monoclonal antibodies allowed us to conclusively identify at least 3 distinct subsets of dendritic cells in skin and to begin to characterize lineage relationships between them. In addition, we have utilized Langerhans cell-deficient mice to identify an unexpected role for these cells in antibody forming responses. Immunization of transgenic mice at a time when they are Langerhans cell deficient via gene gun led to selective attenuation of the IgG1 isotype response. Since IgG1 formation is thought to be IL-4-dependent, this suggests that Langerhans cells may be specialized to present antigen to Th2 cells. How this might occur remains to be determined. These findings are described in a paper that was published in the Proceedings of the National Academy of Sciences in 2009. In ongoing studies, we are using alternative immunization strategies to discern mechanisms that allow Langerhans cells to regulate responses to topically applied protein antigens. The above studies have provided data that has resulted in development of new hypotheses regarding Langerhans cell ontogeny. We have examined the possibility that locally secreted influences that may be keratinocyte-derived may be important regulators of Langerhans cell differentiation. Both in vitro and in vivo approaches were utilized. Results obtained via these studies implicate Wnt-signaling in Langerhans cell development. Relevant findings have been published in the Journal of Investigative Dermatology in 2011. Collaborative studies of dendritic cells and their products in experimental cutaneous leishmaniasis have also continued and results continue to inform our understanding of dendritic cell function in this murine model of an important human disease. Recent results implicate the cytokine IL-17 and neutrophils in Leishmania pathogenesis in susceptible mice. It is anticipated that these insights will promote development of a vaccine that will attenuate the burden of this world-wide health problem. A publication describing these findings was published in the Journal of Immunology in 2009. In additional collaborative studies, the ability of recombinant Leishmania proteins containing the TAT protein transduction domain to serve as vaccine candidates in murine experimental cutaneous leishmaniasis has been tested. These studies indicates the ability to prime CD8 T cells correlates with disease protection and/or attenuation, and the findings were published in the Journal of Investigative Dermatology in 2010. Follow up studies utilizing IL-1 receptor- and IL-1 receptor antagonist (IL-1RA)-deficient mice have additionally characterized the involvement of these entities in the experimental cutaneous leishmaniasis in mice. These results were published in manuscripts appearing in Experimental Dermatology and the Journal of Investigative Dermatology in 2011. An additional collaboration involves Dr. Maria Morasso and her investigative group in NIAMS. Dr. Morasso has developed a novel mouse in which the transcription factor Dlx3 is selectively deleted in keratinocytes. This results in a barrier defect, production of a variety of chemokines and inflammatory mediators by keratinocyes and subsequent development of a systemic inflammatory syndrome that is characterized by prominent IL-17 production. We are playing a major role in the characterization of the inflammation that occurs in these mice. The initial description of the phenotype of these mice appeared in the Proceedings of the National Academy of Sciences in 2011 and additional studies are ongoing. The goal of these studies is to understand the mechanism(s) by which lack of expression of a transcription factor (Dlx3) in keratinocytes results in an inflammatory condition that shares some features with the human skin disease psoriasis. Using neutralizing monoclonal antibodies, we have identified cytokines that are particularly important in this mouse models and leukocytes that produce them. We are in the process of of elucidating the mechanism(s) by which loss of a transcription factor in epidermal keratinocytes leads to production of relevant cytokines by cells of interest. The laboratory has long been interested in elucidating effects of the cytokine TGF beta on epidermal Langerhans cells and dendritic cells. In a recent collaboration with Dr. Adam Glick and co-workers, we helped elucidate effects of over expression of TGF beta in skin on dendritic cell homeostasis in mice. A surprising result was that TGF beta over expression mobilized cutaneous dendritic cells and enhanced contact hypersensitivity reactions. These results and supporting data was published on the Journal of Investigative Dermatology in 2012. A final collaboration involves Dr. Keisuke Nagao and his colleagues at Keio University in Tokyo. In continuing studies that he initiated in my laboratory, Dr. Nagao and co-workers have determined that mouse epidermal Langerhans cells can derive from several different precursors in different settings and, surprisingly, that terminal hair follicles serve as portals of entry into epidermis, very likely reflecting production of selected chemokines by subpopulations of hair follicle keratinocytes. These findings have recently been published in Nature Immunology.

我们对皮肤树突状细胞生理学的长期兴趣仍在继续。最近开发的小鼠是组成型的，或者可以有条件地制成的，兰格汉细胞缺陷率可以对兰格汉斯细胞功能和发育进行明确的研究。这些小鼠菌株之一和多种单克隆抗体使我们能够最终识别皮肤中的树突状细胞的至少3个不同的子集，并开始表征它们之间的谱系关系。此外，我们还利用Langerhans细胞缺陷的小鼠确定这些细胞在形成抗体反应中的意外作用。转基因小鼠在通过基因枪缺乏兰格汉细胞的时候对它们的免疫接种导致IgG1同种型反应的选择性衰减。由于IgG1形成被认为是IL-4依赖性的，因此这表明Langerhans细胞可能专门针对Th2细胞呈现抗原。如何发生这种情况尚待确定。这些发现在2009年美国国家科学院论文集中发表的论文中进行了描述。在正在进行的研究中，我们正在使用替代的免疫策略来识别允许Langerhans细胞调节局部应用蛋白质抗原反应的机制。上述研究提供了有关兰格汉斯细胞个体发育的新假设的发展的数据。我们已经研究了可能是角质形成细胞衍生的本地分泌影响的可能性可能是兰格汉细胞分化的重要调节剂。都使用了体外和体内方法。通过这些研究获得的结果暗示了Langerhans细胞发育中的Wnt信号。相关发现已发表在2011年的《调查性皮肤病学杂志》上。在实验性皮肤利什曼病中，对树突状细胞及其产物的合作研究也在继续，结果继续为我们对这种重要人类疾病的鼠模型中的树突状细胞功能的理解提供了信息。最近的结果暗示了易感小鼠利什曼原虫发病机理中的细胞因子IL-17和中性粒细胞。可以预料，这些见解将促进疫苗的开发，从而减轻这个全球健康问题的负担。描述了这些发现的出版物发表在2009年的《免疫学杂志》上。在其他协作研究中，重组利什曼原虫蛋白包含TAT蛋白质转导域在鼠类实验性皮肤利什曼病中充当疫苗候选物的能力。这些研究表明，CD8 T细胞与疾病的保护和/或衰减相关的能力，发现在2010年的《调查性皮肤病学杂志》中发表了。使用IL-1受体和IL-1受体拮抗剂（IL-1RA）的后续研究，这些研究的范围是这些实体症的参与，并在ceTANE中的参与中加以表征。这些结果发表在2011年实验性皮肤病学和调查性皮肤病学杂志上出现的手稿中。额外的合作涉及玛丽亚·莫拉索（Maria Morasso）博士及其在NIAMS的调查小组。 Morasso博士开发了一种新颖的小鼠，其中转录因子DLX3在角质形成细胞中有选择地删除。这导致屏障缺陷，角质类生物的多种趋化因子和炎症介质产生，以及随后发展的全身性炎症综合征，其特征是IL-17显着的产生。我们在这些小鼠中发生的炎症的表征中发挥了重要作用。这些小鼠表型的最初描述出现在2011年美国国家科学院的会议录中，并且正在进行其他研究。这些研究的目的是了解角质形成细胞中缺乏转录因子（DLX3）表达的机制，导致炎症状况与人类皮肤病牛皮癣具有某些特征。使用中和单克隆抗体，我们发现了在产生它们的小鼠模型和白细胞中特别重要的细胞因子。我们正在阐明表皮角质形成细胞中转录因子损失导致相关细胞因子通过感兴趣的细胞产生相关细胞因子的机制。该实验室长期以来一直对阐明细胞因子TGFβ对表皮兰格汉细胞和树突状细胞的影响感兴趣。在最近与亚当·格里克（Adam Glick）博士和同事的一项合作中，我们帮助阐明了TGFβ在皮肤对小鼠树突状细胞稳态中的过度表达的影响。一个令人惊讶的结果是，TGFβ上的表达动员性皮肤树突状细胞并增强了接触性超敏反应。这些结果和支持数据在2012年发表了《调查性皮肤病学杂志》上。最终的合作涉及Nagao博士及其同事在东京的Keio大学。在他在我的实验室中发起的继续研究中，Nagao博士及其同事确定小鼠表皮langerhans细胞可以在不同情况下从几个不同的前体中得出，而且令人惊讶的是，终末毛囊作为进入表皮的门户，很可能反映出通过毛毛皮质体的毛囊来反映所选趋化因子的产生。这些发现最近在自然免疫学上发表。