Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse

靶向 IRE-1a/XBP-1 轴控制慢性 GVHD 和白血病复发

• 批准号: 10179448
• 负责人: Xue-Zhong Yu
• 金额: $ 7.28万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-01-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10179448
• 关键词: ATF6 gene; Allogeneic Bone Marrow Transplantation; Allogenic; Antibodies; Antibody Formation; Antigen-Presenting Cells; Apoptosis; Area; B Cell Proliferation; B-Cell Activation; B-Cell Leukemia; B-Lymphocytes; Binding Proteins; Biology; Blood; Cells; Cellular Stress Response; Cellular biology; Chronic; Clinic; Complication; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Development; Disease; Endoplasmic Reticulum; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic Stem Cell Transplantation; Immune; Immune response; Immune system; Incidence; Leukemic Cell; Lymphocyte Function; Malignant Neoplasms; Messenger RNA; Molecular; Morbidity - disease rate; Multiple Myeloma; Mus; Nuclear; Patients; Pharmacology; Play; Pre-Clinical Model; Prevention; Prophylactic treatment; Proteins; Publishing; RNA Splicing; Recurrence; Regimen; Research; Role; Severities; Severity of illness; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic Effect; Translating; Transplantation; chronic graft versus host disease; defined contribution; design; endoplasmic reticulum stress; genetic approach; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; inhibitor/antagonist; leukemia; leukemia relapse; leukemia/lymphoma; mortality; novel; novel therapeutics; plasma cell differentiation; preservation; prophylactic; protein degradation; protein folding; response; therapeutic target; transcription factor

Abstract Hematological malignancies that include leukemia and lymphoma are often treated with allogeneic hematopoietic stem cell transplantation (allo-HCT). However, chronic graft-versus-host disease (cGVHD) remains a prominent cause of transplant-related morbidity and mortality despite available immunosuppressive regimens. Few prophylactic strategies have been successful at reducing the incidence of cGVHD in patients after allo-HCT. An area previously unexplored as a treatment for cGVHD involves the unfolded protein response (UPR). Three master regulators control the UPR: PERK, IRE-1α, and ATF6. When IRE-1α becomes activated, its primary function is to splice Xbox binding protein-1 (XBP-1u) mRNA. Spliced XBP-1 (XBP-1s) mRNA is translated into XBP-1 protein which acts as an effective nuclear transcription factor. Immune responses such as B-cell proliferation and antibody production require large amounts of properly folded proteins. As a transcription factor, XBP-1 protein relieves ER stress by up regulating cellular machinery responsible for protein folding and degradation. XBP-1 is therefore required for the effector function and survival of various types of immune cells that are susceptible to ER stress. IRE-1α/XBP-1 signaling axis plays predominate roles in B cells and dendritic cells (DCs) among other immune cells. Built upon published findings and our preliminary observations, we will evaluate how IRE-1α/XBP-1 signaling axis impacts in the development of cGVHD after allo-HCT through regulating B cells and DCs among others. Our Central Hypothesis is that XBP-1 plays an essential role for B-cell and DC activation and function, and targeting XBP-1 will restrain allogeneic responses leading to the control of cGVHD while preserving the integrity of cytotoxic T lymphocytes (CTL) and thus maintaining the graft-versus-leukemia (GVL) effect. This hypothesis will be tested in the following two Specific Aims: 1) Define the contribution of XBP-1 on hematopoietic cells in the development of cGVHD after allo-HCT using a genetic approach; 2) Determine the therapeutic effect of targeting XBP-1 in the control of cGVHD and leukemia relapse using a pharmacological approach. The current study is expected to further understand the cell biology how UPR regulates immune responses, reveal the role for IRE-1α/XBP-1 signaling axis in the development of cGVHD and relatable hematologic malignancies, and provide a novel therapy for controlling cGVHD and leukemia relapse in after allo-HCT.

摘要 包括白血病和淋巴瘤在内的血液系统恶性肿瘤通常用异基因移植治疗。 造血干细胞移植(allo-HCT)。然而，慢性移植物抗宿主病(CGVHD) 仍然是移植相关发病率和死亡率的主要原因，尽管有可用的免疫抑制剂 养生法。很少有预防策略能成功降低患者cGVHD的发生率 在allo-hct之后。一个先前未被探索用于治疗慢性移植物抗宿主病的领域涉及未折叠的蛋白质。 回应(普遍定期审议)。三个主调节器控制着UPR：PERK、IRE-1α和ATF6。当IRE-1\f25α-1\f6变为 激活后，其主要功能是剪接Xbox结合蛋白-1(XBP-1U)的mRNA。剪接XBP-1(XBP-1S) MRNA被翻译成XBP-1蛋白，作为一种有效的核转录因子。免疫 B细胞的增殖和抗体的产生等反应需要大量的适当折叠 蛋白质。作为一种转录因子，XBP-1蛋白通过上调细胞机械来缓解内质网应激 负责蛋白质的折叠和降解。因此，效应器功能需要XBP-1 对内质网应激敏感的各种免疫细胞的存活。IRE-1α/XBP-1信号轴发挥作用 在其他免疫细胞中，B细胞和树突状细胞(DC)起主要作用。以已发表的研究结果为基础 和我们的初步观察，我们将评估IRE-1α/XBP-1信号轴在 异基因造血干细胞移植后通过调节B细胞和DC等发生移植物抗宿主病。我们的中环 假设XBP-1在B细胞和DC的激活和功能中起重要作用，并以XBP-1为靶点 将抑制导致控制cGVHD的同种异体反应，同时保持细胞毒性T细胞的完整性 从而维持移植物抗白血病(GVL)效应。这一假设将得到检验。 在以下两个具体目标中：1)确定XBP-1对小鼠造血细胞的贡献 采用遗传学方法进行allo-HCT后cGVHD的发生；2)确定治疗效果 使用药理学方法靶向XBP-1控制cGVHD和白血病复发。海流 这项研究有望进一步了解细胞生物学中UPR如何调节免疫反应，揭示其作用 IRE-1、α/XBP-1信号轴在慢性移植物抗宿主病和相关血液系统恶性肿瘤的发生发展中的作用 为控制异基因造血干细胞移植后cGVHD和白血病复发提供一种新的治疗方法。