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

Delta样配体4树突状细胞和同种免疫的诱导

基本信息

批准号：
9207071
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207071
关键词：
Adoptive Transfer Allogeneic Bone Marrow Transplantation Allogenic Antigens Autoimmune Diseases Biological Blood Bone Marrow Cells CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD80 gene CD86 gene CD8B1 gene Cell Differentiation process Cells Characteristics Complication Cultured Cells Cytotoxic T-Lymphocytes Data Dendritic Cells Development Disease Disease model Effector Cell Employee Strikes FLT3LG gene Frequencies Generations Goals Graft Rejection Graft-Versus-Tumor Induction Granulocyte-Macrophage Colony-Stimulating Factor Growth Hematologic Neoplasms Hematological Disease Hematopoietic Stem Cell Transplantation IL6 gene Immune 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 Pathway interactions Patients Peptides Peripheral Phenotype Play Procedures Production Property Receptor Signaling Relapse Resistance Role STAT3 gene Signal Transduction Solid Specificity Surface T cell response T-Lymphocyte TNF gene Toll-like receptors Transcript Treatment Failure Tumor Antigens Tumor Immunity adaptive immunity arginase clinically relevant curative treatments 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 therapeutic intervention organ transplant rejection public health relevance response tumor

项目摘要

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（由申请人提供）：同种异体造血干细胞移植（allo-HSCT）是一种治疗许多对其他疗法耐药的血液恶性肿瘤的方法，这种有益的抗肿瘤活性主要来自输注的供体 T 细胞，称为移植物抗肿瘤。（GVT）效应。然而，复发仍然是高危血液恶性肿瘤患者异基因造血干细胞移植（allo-HSCT）治疗失败的主要原因。 GVT 效应缺乏特异性，与危及生命的移植物抗宿主病 (GVHD) 并发症密切相关，迫切需要新的方法来改善 GVT，同时限制异基因 HSCT 信号可能在外周血中发挥多种重要作用。 T 细胞反应。使用 allo-HSCT 小鼠模型，我们发现：1）Notch 缺失的供体 T 细胞产生效应细胞因子（例如 IFN-γ、 TNF-α 和 IL-17）并未能引起 GVHD，表明 Notch 途径在 GVHD 诱导过程中，受体树突状细胞 (DC) 的表面增加，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 表达更高水平的 Dll4+DC。 CD80 和 CD86 增加了 IL6 和 IL23 mRNA，但减少了 IL12、IL21 和精氨酸酶 1 的转录物。抑制 Dll4 导致减少此外，抗 Dll4 抗体 (Ab) 的体内治疗可抑制 GVHD，因此，Notch 信号传导的 Dll4 激活对于 GVH 反应非常重要。对于从培养的骨髓细胞中诱导 Dll4+DC 至关重要，抑制 NF-κB 信号可阻断 Flt3L 诱导的 DC 中 Dll4 的表达； 4) Flt3L诱导的Dll4+DC比GM-CSF诱导的Dll4-DC具有更大的促进CD4+T辅助细胞(Th)1和Th17细胞分化的能力，其转移装载有肿瘤抗原肽的Flt3L诱导的Dll4+DC。诱导有效的 CD8+ T 细胞介导的抗肿瘤活性因此，我们认为 Dll4+DC 是以前未表征的炎症 DC，对于诱导 GVHD 和 GVT 很重要。提出具体目标来确定这一假设。第一个目标是，我们计划使用小鼠 GVHD 模型来鉴定 Dll4+DC 的表型和功能特征及其在介导 GVHD 中的重要作用。我们将研究 STAT3 是否以及如何与 NF-κB 信号相互作用来控制 DC 中 Dll4 的表达，从而对 Dll4+DC 的发育进行分子研究。最终目标是确定调节 Dll4+DC 对改善异基因 HSCT 和白血病小鼠 GVT 的有益作用。增强 GVT 同时限制 GVHD，了解 Dll4+DC 在同种免疫中的作用将导致开发新的临床相关方法来增强抗肿瘤免疫，这可能对大约有潜在益处。每年有 10,000 名新患者接受异基因造血干细胞移植，鉴于树突状细胞在适应性免疫中的核心作用，这些研究的结果可能对改善肿瘤免疫和控制其他炎症性疾病（例如移植器官的排斥反应）具有重要意义。广义上的自身免疫性疾病。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

New insights into the basic biology of acute graft-versus-host-disease.

对急性移植物抗宿主病基础生物学的新见解。

DOI：
发表时间：
2020
期刊：
影响因子：
10.1
作者：
Li, Alicia;Abraham, Ciril;Wang, Ying;Zhang, Yi
通讯作者：
Zhang, Yi

Epigenetic Regulation of Dendritic Cell Development and Function.

树突状细胞发育和功能的表观遗传调控。

DOI：
10.1097/ppo.0000000000000280
发表时间：
2017
期刊：
Cancer journal
影响因子：
2.2
作者：
Tian Y;Meng L;Zhang Y
通讯作者：
Zhang Y

Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells.

间充质干细胞通过诱导调节性树突状细胞减轻细菌引起的小鼠肝损伤。

DOI：
发表时间：
2014-02
期刊：
影响因子：
0
作者：
Zhang, Yi;Cai, Wei;Huang, Qingrong;Gu, Yuting;Shi, Yufang;Huang, Jiefang;Zhao, Fang;Liu, Qiang;Wei, Xunbin;Jin, Min;Wu, Changping;Xie, Qing;Zhang, Yi;Wan, Bing;Zhang, Yanyun
通讯作者：
Zhang, Yanyun

Metabolic Diseases Downregulate the Majority of Histone Modification Enzymes, Making a Few Upregulated Enzymes Novel Therapeutic Targets--"Sand Out and Gold Stays".

代谢性疾病下调大部分组蛋白修饰酶，使少数上调酶成为新的治疗靶点——“出沙金留”。

DOI：
发表时间：
2016-02
期刊：
影响因子：
0
作者：
Shao, Ying;Chernaya, Valeria;Johnson, Candice;Yang, William Y;Cueto, Ramon;Sha, Xiaojin;Zhang, Yi;Qin, Xuebin;Sun, Jianxin;Choi, Eric T;Wang, Hong;Yang, Xiao
通讯作者：
Yang, Xiao

Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in mice.

Delta 样配体 4 识别了先前未表征的炎症树突细胞群，该细胞在引发小鼠同种异体 T 细胞反应中发挥重要作用。

DOI：
发表时间：
2013-04-01
期刊：
影响因子：
0
作者：
Mochizuki, Kazuhiro;Xie, Fang;He, Shan;Tong, Qing;Liu, Yongnian;Mochizuki, Izumi;Guo, Yajun;Kato, Koji;Yagita, Hideo;Mineishi, Shin;Zhang, Yi
通讯作者：
Zhang, Yi