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: 7969728
• 负责人: Mark Udey
• 金额: $ 31.89万
• 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/7969728
• 关键词: Adjuvant; Annual Reports; Antibodies; Antigen-Presenting Cells; Antigens; Area; Attenuated; Blood; Cell Differentiation process; Cell Ontogeny; Cell physiology; Cells; Cutaneous; Cutaneous Leishmaniasis; Data; Dendritic Cells; Development; Disease; Goals; Growth; Health; Human; IgG1; Immune; Immune response; Immunization; Immunology; In Vitro; Interleukin-17; Journals; Laboratories; Langerhans cell; Leishmania; Malignant Neoplasms; Modeling; Monoclonal Antibodies; Mouse Strains; Mus; Nature; Organ; Paper; Pathogenesis; Patients; Process; Publications; Publishing; Regulation; Reporting; Role; Skin; T-Cell Lymphoma; T-Cell Receptor; T-Lymphocyte; Testing; Th2 Cells; Time; Transgenic Mice; Tumor Antigens; United States National Academy of Sciences; Vaccines; alpha-beta T-Cell Receptor; attenuation; base; cytokine; gene gun; genetic vaccine; human disease; in vivo; insight; interest; keratinocyte; neutrophil; novel; receptor; response; subcutaneous; tumor; vaccination strategy; 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 for the first time. Using one of these strains of mice and a variety of monoclonal antibodies have 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 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 leads 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 has been published in the Proceedings of the National Academy of Sciences since submission of the last annual report. The above studies have provided data that has resulted in development of new hypotheses regarding Langerhans cell ontogeny. We are in the process of examining 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 are being utilized in these studies. Another project area that has been actively pursued in the laboratory involves testing the feasibility of using T cell receptor proteins expressed by clonal T cell malignancies as tumor antigens in vaccines. DNA-based (genetic vaccination) strategies are being emphasized because of concerns regarding the practicality of patient-specific therapies. A reproducible model involving subcutaneous growth of T cell lymphomas in mice has been established in the laboratory. cDNAs encoding T cell receptor alpha and beta chains from this murine T cell lymphoma have been cloned and sequenced, and several candidate vaccines have been generated. We have determined that several candidate vaccines have activity. In the course of these studies, we identified a novel adjuvant strategy that dramatically increases the efficacy of TCR-based vaccines. We have also shown that this strategy can be generalized, both with regard to the nature of the helper antigen and to the tumor and corresponding tumor antigen. Because we anticipate that this adjuvant strategy will be generally applicable and well tolerated, incorporation into human vaccine trials may be feasible. A publication describing these findings has appeared in the journal Blood since the last annual report was submitted. Collaborative studies of dendritic cells and their products in experimental cutaneous leishmaniasis are also ongoing, 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 this reporting period.

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，或可以有条件地制成的，兰格汉细胞缺陷率可以首次对兰格汉细胞功能和发育进行确定的研究。使用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细胞缺陷来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会导致对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。 这些发现在上次年度报告提交以来已经在美国国家科学院会议录中发表的论文中进行了描述。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。我们正在研究可能是角质形成细胞的本地分泌影响可能是Langerhans细胞分化的重要调节剂的可能性。在这些研究中，都使用了体外和体内方法。 在实验室中积极追求的另一个项目区域涉及测试使用由克隆T细胞恶性肿瘤表达的T细胞受体蛋白作为疫苗中肿瘤抗原的可行性。由于对患者特异性疗法的实用性的担忧，因此强调了基于DNA的（遗传疫苗接种）策略。在实验室已经建立了一个涉及小鼠T细胞淋巴瘤皮下生长的可重复模型。已将该鼠T细胞淋巴瘤的T细胞受体α和β链编码T细胞受体α和β链的cDNA被克隆并测序，并产生了几种候选疫苗。 我们已经确定几种候选疫苗具有活性。在这些研究过程中，我们确定了一种新型的辅助策略，该策略大大提高了基于TCR的疫苗的功效。我们还表明，在辅助抗原的性质和肿瘤和相应的肿瘤抗原方面都可以推广该策略。因为我们预计这种辅助策略通常适用且容忍良好，所以将人类疫苗试验纳入可能是可行的。自上次年度报告提交以来，杂志的血液中出现了一份描述这些发现的出版物。 在实验性皮肤利什曼病中对树突状细胞及其产物的协作研究也在进行中，结果在这种重要的人类疾病的鼠模型中，结果继续为我们对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。描述这些发现的出版物在本报告期间发表在《免疫学杂志》上。