Delta-like ligand 4+ dendritic cells and induction of alloimmunity

Delta样配体4树突状细胞与同种免疫的诱导

• 批准号: 8787454
• 负责人: YI ZHANG
• 金额: $ 32.37万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-15 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787454
• 关键词: Allogeneic Bone Marrow Transplantation; Allogenic; Antigens; Autoimmune Diseases; Biological; Blood; Bone Marrow Cells; CD4 Positive T Lymphocytes; CD80 gene; CD8B1 gene; Cell Culture Techniques; Cell Differentiation process; Cells; Characteristics; Complication; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Disease model; Effector Cell; Employee Strikes; Frequencies; Generations; Goals; Graft Rejection; Graft-Versus-Tumor Induction; Granulocyte-Macrophage Colony-Stimulating Factor; Growth; Health; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Transplantation; IL6 gene; Immune; Immunity; Inflammatory; Interferon Type II; Interleukin-12; Interleukin-17; Interleukin-6; Lead; Life; Ligands; Link; Malignant Neoplasms; Mediating; Messenger RNA; Methods; Minor; Molecular; Mus; NF-kappa B; Names; Organ; Organ Transplantation; Pathway interactions; Patients; Peptides; Peripheral; Play; Procedures; Production; Property; Receptor Signaling; Relapse; Resistance; Role; STAT3 gene; Signal Transduction; Solid; Specificity; Surface; T cell response; T-Lymphocyte; Toll-like receptors; Transcript; Transplantation; Treatment Failure; Tumor Antigens; Tumor Immunity; Tumor Necrosis Factor-alpha; adaptive immunity; arginase; clinically relevant; cytokine; design; graft versus host disease induction; graft vs host disease; high risk; improved; in vivo; inhibiting antibody; insight; interleukin-21; isoimmunity; leukemia; mouse model; neoplastic cell; notch protein; novel; novel strategies; novel therapeutics; response; tumor

DESCRIPTION (provided by applicant): Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematological malignancies resistant to other therapies. This beneficial anti-tumor activity largely derives from infused donor T cells, named graft-versus-tumor (GVT) effect. However, relapse remains a major cause of treatment failure of allo-HSCT for patients with high-risk hematological malignancies. In addition, the GVT effect lacks specificity and is tightly linked to a life-threatening complication of graft-versus-host disease (GVHD). Novel approaches are urgently needed to improve GVT while limiting GVHD after allo-HSCT. Notch signaling may play multiple important roles in peripheral T cell responses. Using mouse models of allo-HSCT, we discovered that: 1) Notch-deprived donor T cells showed drastically reduced ability to produce effector cytokines (e.g., IFN-γ, TNF-α and IL-17) and failed to cause GVHD, suggesting that the Notch pathway increased on the surface of a subset of recipient dendritic cells (DCs) during GVHD induction. We named these Dll4-positive DCs as Dll4+DCs. As compared to Dll4-negative DCs (Dll4-DCs), Dll4+DCs expressed higher levels of CD80 and CD86, had increased IL6 and IL23 mRNA but reduced transcripts of IL12, IL21 and Arginase 1. Inhibition of Dll4 caused a reduction in frequency of alloreactive effector T cells activated by allogeneic DCs. Furthermore, in vivo treatment with anti-Dll4 antibody (Ab) inhibited GVHD. Thus, Dll4 activation of Notch signaling is important for GVH responses; 3) Flt3L and Toll-like receptor signaling were essential for induction of Dll4+DCs from cultured bone marrow cells. Inhibition of NF-κB signaling blocked the expression of Dll4 in Flt3L-induced DCs; 4) Flt3L-induced Dll4+DCs had greater ability than GM-CSF-induced Dll4-DCs to promote CD4+ T helper (Th)1 and Th17 cell differentiation. Transfer of Flt3L-induced Dll4+DCs that were loaded with tumor antigen-peptide induced potent CD8+ T cell-mediated antitumor activity. Thus, we hypothesize that Dll4+DCs are previously uncharacterized inflammatory DCs important for the induction of GVHD and GVT. Three specific aims are proposed to determine this hypothesis. In the first aim, we plan to use mouse GVHD models to identify the phenotypic and functional characteristics of Dll4+DCs and their important roles in mediating GVHD. The second aim is designed to define the mechanisms that regulate the development of Dll4+DCs. We will examine whether and how STAT3 interacts with NF-κB signaling to control the expression of Dll4 in DCs. Molecular insights into the development of Dll4+DCs may lead to the identification of novel targets for modulating GVH responses. The final aim will be to establish the beneficial effects of modulating Dll4+DCs on improving GVT in mice of allo-HSCT and leukemia. The goal of this aim is to design a new therapeutic strategy to augment GVT while limiting GVHD. Understanding the role of Dll4+DCs in alloimmunity will lead to the development of novel and clinically relevant approaches to augment antitumor immunity, which could be potentially beneficial to approximately 10,000 new patients who receive allo-HSCT every year. Given the central role of DCs in adaptive immunity, results from these studies may have significant implications in the improvement of tumor immunity and control of other inflammatory disorders such as graft-rejection of transplanted organs and autoimmune diseases in broad context.

描述（由应用提供）：同种异体造血干细胞移植（Allo-HSCT）是一种治疗方法，可用于许多对其他疗法的血液学恶性肿瘤。这种有益的抗肿瘤活性在很大程度上源自注入的供体T细胞，该细胞称为移植物 - 及格肿瘤（GVT）效应。然而，对于高风险血液系统恶性肿瘤患者，复发仍然是同种HSCT治疗失败的主要原因。此外，GVT效应缺乏特异性，并且与危及生命的抗性抗宿主病（GVHD）的并发症紧密相关。迫切需要采用新颖的方法来改善GVT，同时限制Allo-HSCT之后的GVHD。 Notch信号传导可能在外围T细胞响应中起多个重要作用。使用Allo-HSCT的鼠标模型，我们发现：1）缺口剥夺的供体T细胞显示出产生效应子细胞因子的能力（例如IFN-γ，TNF-α和IL-17），并未引起GVHD，表明Notch途径未能引起GGVHD。 GVHD诱导过程中受体树突状细胞（DC）的一部分表面增加。我们将这些DLL4阳性DC命名为DLL4+DC。与DLL4阴性DC（DLL4-DC）相比，DLL4+DC表达的CD80和CD86水平较高，IL6和IL23 mRNA增加了，但是IL12，IL21和精氨酸酶1的转录减少了DLL4的DLL4的抑制作用导致Alloreactive ailogective Allog Timence yc降低DL的频率。此外，用抗DLL4抗体（AB）抑制GVHD的体内治疗。那就是Notch信号的DLL4激活对于GVH响应很重要。 3）FLT3L和TOLL样受体信号传导对于从培养的骨髓细胞中诱导DLL4+DC至关重要。 NF-κB信号传导的抑制阻止了FLT3L诱导的DC中DLL4的表达。 4）FLT3L诱导的DLL4+ DC的能力高于GM-CSF诱导的DLL4-DC促进CD4+ T助手（Th）1和Th17细胞分化的能力。装有肿瘤抗原肽诱导的潜在CD8+ T细胞介导的抗肿瘤活性的FLT3L诱导的DLL4+ DC的转移。这是我们假设DLL4+DC先前是未表征的炎症DCS对GVHD和GVT诱导很重要的。提出了三个具体目标来确定这一假设。在第一个目标中，我们计划使用小鼠GVHD模型来识别DLL4+DC的表型和功能特征及其在中介GVHD中的重要作用。第二个目标旨在定义调节DLL4+DC发展的机制。我们将检查STAT3是否以及如何与NF-κB信号传导相互作用，以控制DCS中DLL4的表达。对DLL4+DC的发展的分子见解可能导致鉴定用于调节GVH响应的新靶标。最终目的是建立调节DLL4+DC对改善Allo-HSCT和白血病小鼠GVT的有益作用。该目标的目的是设计一种新的理论策略，以增强GVT，同时限制GVHD。了解DLL4+DC在同种免疫性中的作用将导致开发新颖和临床相关的方法来增强抗肿瘤免疫学，这可能对每年接受Allo-HSCT的大约10,000名新患者有益。鉴于DC在适应性免疫学中的核心作用，这些研究的结果可能对改善肿瘤免疫学和控制其他炎症性疾病的控制具有显着影响，例如在广泛的情况下移植了移植器官和自身免疫性疾病。