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: 10578550
• 负责人: Xue-Zhong Yu
• 金额: $ 51.28万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10578550
• 关键词: Targeting; IRE; 1a; XBP; Axis

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.

抽象的 包括白血病和淋巴瘤在内的血液性恶性肿瘤通常用同种异体治疗 造血干细胞移植（Allo-HCT）。但是，慢性移植抗宿主病（CGVHD） 仍然是与移植相关的发病率和死亡率目的地的重要原因，可用免疫抑制 方案。很少有预防性策略成功地减少患者的CGVHD事件 在Allo-HCT之后。以前未经探索的区域作为CGVHD的治疗涉及展开的蛋白 响应（UPR）。三个主调节器控制UPR：PERK，IRE-1α和ATF6。当IRE-1α变为时 激活的主要功能是剪接Xbox结合蛋白-1（XBP-1U）mRNA。剪接的XBP-1（XBP-1） mRNA被翻译成XBP-1蛋白，该蛋白充当有效的核转录因子。免疫 诸如B细胞增殖和抗体产生之类的反应需要大量正确折叠 蛋白质。作为转录因子，XBP-1蛋白通过提高调节性细胞机制挽救了ER应力 负责蛋白质折叠和降解。因此，XBP-1是效应子函数需要的 容易受到质心质网应激的各种类型免疫细胞的存活。 IRE-1α/XBP-1信号传导轴播放 与其他免疫细胞相比，在B细胞和树突细胞（DC）中占主导作用。建立在已发表的发现之上 和我们的初步观察，我们将评估IRE-1α/XBP-1信号轴如何影响 通过调节B细胞和DC等，在Allo-HCT后开发CGVHD。我们的中心 假设是XBP-1对于B细胞和直流激活和功能起着至关重要的作用，并且针对XBP-1 将限制同种异反应，从而导致CGVHD控制，同时保留细胞毒性T的完整性 淋巴细胞（CTL），从而维持移植物与白血病（GVL）效应。该假设将进行检验 在以下两个具体目的中：1）定义XBP-1对造血细胞的贡献 使用遗传方法在Allo-HCT后开发CGVHD； 2）确定 使用药物方法来靶向XBP-1在CGVHD和白血病继电器控制中。电流 预计研究将进一步了解UPR调节免疫反应的细胞生物学，揭示了该作用 对于IRE-1α/XBP-1信号轴，在CGVHD的发展和相关的血液恶性肿瘤的发展中 在Allo-HCT之后，提供了一种用于控制CGVHD和白血病中继的新型疗法。