Acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), a potentially curative treatment for leukemia. Endoplasmic reticulum (ER) stress occurs when the protein folding capacity of the ER is oversaturated. How ER stress modulates tissue homeostasis in the context of alloimmunity is not well understood. We show that ER stress contributes to intestinal tissue injury during GVHD and can be targeted pharmacologically. We observed high levels of ER stress upon GVHD onset in a murine allo-HCT model and in human biopsies. These levels correlated with GVHD severity, underscoring a novel therapeutic potential. Elevated ER stress resulted in increased cell death of intestinal organoids. In a conditional knockout model, deletion of the ER stress regulator transcription factor Xbp1 in intestinal epithelial cells induced a general ER stress signaling disruption and aggravated GVHD lethality. This phenotype was mediated by changes in the production of anti-microbial peptides and the microbiome composition as well as activation of pro-apoptotic signaling. Inhibition of inositol-requiring enzyme 1 alpha (IRE1α), the most conserved signaling branch in ER stress, reduced GVHD development in mice. IRE1α blockade by the small molecule inhibitor 4µ8c improved intestinal cell viability, without impairing hematopoietic regeneration and T cell activity against tumor cells. Our findings in patient samples and mice indicate that excessive ER stress propagates tissue injury during GVHD. Reducing ER stress could improve the outcome of patients suffering from GVHD.

中文翻译：

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急性移植物抗宿主病中内质网应激的治疗靶向。

急性移植物抗宿主病 (GVHD) 是同种异体造血细胞移植 (allo-HCT) 的一种危及生命的并发症，是一种潜在的白血病治疗方法。当 ER 的蛋白质折叠能力过饱和时，就会发生内质网 (ER) 应激。ER 应激如何在同种免疫背景下调节组织稳态尚不清楚。我们表明，ER 应激有助于 GVHD 期间的肠道组织损伤，并且可以在药理学上靶向。我们在小鼠 allo-HCT 模型和人体活检中观察到 GVHD 发作时的高水平 ER 应激。这些水平与 GVHD 严重程度相关，强调了一种新的治疗潜力。升高的内质网应激导致肠道类器官的细胞死亡增加。在条件淘汰模型中，肠上皮细胞中 ER 应激调节转录因子 Xbp1 的缺失诱导了一般的 ER 应激信号中断并加重了 GVHD 致死率。这种表型是由抗微生物肽的产生和微生物组组成的变化以及促凋亡信号的激活介导的。抑制需要肌醇的酶 1 α (IRE1α)，这是 ER 应激中最保守的信号分支，减少了小鼠的 GVHD 发展。小分子抑制剂 4µ8c 对 IRE1α 的阻断提高了肠道细胞的活力，而不损害造血再生和 T 细胞对肿瘤细胞的活性。我们在患者样本和小鼠中的发现表明，过度的 ER 应激会在 GVHD 期间传播组织损伤。减少 ER 压力可以改善 GVHD 患者的预后。