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恶性肿瘤通常采用同种异体治疗 造血干细胞移植（allo-HCT）然而，慢性移植物抗宿主病（cGVHD）。 尽管有可用的免疫抑制药物，但它仍然是移植相关发病率和死亡率的一个主要原因 很少有预防策略能够成功降低患者 cGVHD 的发生率。 allo-HCT 后，先前未探索的 cGVHD 治疗领域涉及未折叠蛋白。 当 IRE-1α 变为时，三个主调节器控制 UPR：PERK、IRE-1α 和 ATF6。 激活后，其主要功能是剪接 Xbox 结合蛋白-1 (XBP-1u) mRNA。 mRNA 被翻译成 XBP-1 蛋白，作为有效的核转录因子。 B 细胞增殖和抗体产生等反应需要大量正确折叠的 作为一种转录因子，XBP-1 蛋白通过上调细胞机制​​来缓解 ER 应激。 因此，XBP-1 负责蛋白质折叠和降解，是效应子功能所必需的。 易受 ER 应激影响的各类免疫细胞的存活。 在其他免疫细胞中，B 细胞和树突状细胞 (DC) 中起主导作用 基于已发表的研究结果。 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 等来控制异基因 HCT 后 cGVHD 的发展。 假设 XBP-1 对于 B 细胞和 DC 的激活和功能发挥重要作用，并且靶向 XBP-1 将抑制同种异体反应，从而控制 cGVHD，同时保留细胞毒性 T 的完整性 淋巴细胞（CTL），从而维持移植物抗白血病（GVL）效应，这一假设将得到检验。 以下两个具体目标： 1) 定义 XBP-1 对造血细胞的贡献 使用遗传方法确定异基因 HCT 后 cGVHD 的治疗效果； 使用药理学方法靶向 XBP-1 控制 cGVHD 和白血病复发。 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-1α/XBP-1 信号轴在 cGVHD 和相关血液恶性肿瘤发生过程中的作用，以及 为allo-HCT后控制cGVHD和白血病复发提供了一种新疗法。