Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Tampa, FL, United States.
Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States.
Front Immunol. 2018 Dec 6;9:2887. doi: 10.3389/fimmu.2018.02887. eCollection 2018.
Acute graft- vs. -host disease (GVHD) is an important cause of morbidity and death after allogeneic hematopoietic cell transplantation (HCT). We identify a new approach to prevent GVHD that impairs monocyte-derived dendritic cell (moDC) alloactivation of T cells, yet preserves graft- vs.-leukemia (GVL). Exceeding endoplasmic reticulum (ER) capacity results in a spliced form of X-box binding protein-1 (XBP-1s). XBP-1s mediates ER stress and inflammatory responses. We demonstrate that siRNA targeting XBP-1 in moDCs abrogates their stimulation of allogeneic T cells. B-I09, an inositol-requiring enzyme-1α (IRE1α) inhibitor that prevents XBP-1 splicing, reduces human moDC migration, allo-stimulatory potency, and curtails moDC IL-1β, TGFβ, and p40 cytokines, suppressing Th1 and Th17 cell priming. B-I09-treated moDCs reduce responder T cell activation via calcium flux without interfering with regulatory T cell (Treg) function or GVL effects by cytotoxic T lymphocytes (CTL) and NK cells. In a human T cell mediated xenogeneic GVHD model, B-I09 inhibition of XBP-1s reduced target-organ damage and pathogenic Th1 and Th17 cells without impacting donor Tregs or anti-tumor CTL. DC XBP-1s inhibition provides an innovative strategy to prevent GVHD and retain GVL.
急性移植物抗宿主病（GVHD）是异基因造血细胞移植（HCT）后发病率和死亡率的重要原因。我们发现了一种新的方法来预防 GVHD，这种方法会损害单核细胞衍生的树突状细胞（moDC）对 T 细胞的同种异体激活，但保留移植物抗白血病（GVL）。内质网（ER）容量超过会导致 X 盒结合蛋白-1（XBP-1）的剪接形式。XBP-1 介导 ER 应激和炎症反应。我们证明，针对 moDC 中的 XBP-1 的 siRNA 可消除其对同种异体 T 细胞的刺激。B-I09 是一种肌醇需求酶-1α（IRE1α）抑制剂，可防止 XBP-1 剪接，减少人 moDC 的迁移、同种刺激能力，并限制 moDC 的 IL-1β、TGFβ 和 p40 细胞因子，从而抑制 Th1 和 Th17 细胞的启动。B-I09 处理的 moDC 通过钙通量减少反应性 T 细胞的激活，而不干扰调节性 T 细胞（Treg）功能或细胞毒性 T 淋巴细胞（CTL）和 NK 细胞的 GVL 效应。在人类 T 细胞介导的异种 GVHD 模型中，B-I09 抑制 XBP-1s 减少了靶器官损伤和致病性 Th1 和 Th17 细胞，而不影响供体 Treg 或抗肿瘤 CTL。DC XBP-1s 抑制为预防 GVHD 和保留 GVL 提供了一种创新策略。
