Teshima Takanori, Reddy Pavan, Zeiser Robert
Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Biol Blood Marrow Transplant. 2016 Mar;22(3 Suppl):S3-8. doi: 10.1016/j.bbmt.2016.01.004.
Graft-versus-host disease (GVHD) continues to be a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Recent insights into intestinal homeostasis and uncovering of new pathways and targets have greatly reconciled our understanding of GVHD pathophysiology and will reshape contemporary GVHD prophylaxis and treatment. Gastrointestinal (GI) GVHD is the major cause of mortality. Emerging data indicate that intestinal stem cells (ISCs) and their niche Paneth cells are targeted, resulting in dysregulation of the intestinal homeostasis and microbial ecology. The microbiota and their metabolites shape the immune system and intestinal homeostasis, and they may alter host susceptibility to GVHD. Protection of the ISC niche system and modification of the intestinal microbiota and metabolome to restore intestinal homeostasis may, thus, represent a novel approach to modulate GVHD and infection. Damage to the intestine plays a central role in amplifying systemic GVHD by propagating a proinflammatory cytokine milieu. Molecular targeting to inhibit kinase signaling may be a promising approach to treat GVHD, ideally via targeting the redundant effect of multiple cytokines on immune cells and enterocytes. In this review, we discuss insights on the biology of GI GVHD, interaction of microflora and metabolome with the hosts, identification of potential new target organs, and identification and targeting of novel T cell-signaling pathways. Better understanding of GVHD biology will, thus, pave a way to develop novel treatment strategies with great clinical benefits.
移植物抗宿主病（GVHD）仍然是异基因造血干细胞移植后发病和死亡的主要原因。最近对肠道稳态的深入了解以及新途径和靶点的发现，极大地增进了我们对GVHD病理生理学的理解，并将重塑当代GVHD的预防和治疗。胃肠道（GI）GVHD是死亡的主要原因。新出现的数据表明，肠道干细胞（ISC）及其生态位潘氏细胞是靶点，导致肠道稳态和微生物生态失调。微生物群及其代谢产物塑造免疫系统和肠道稳态，它们可能改变宿主对GVHD的易感性。因此，保护ISC生态位系统以及调节肠道微生物群和代谢组以恢复肠道稳态，可能代表一种调节GVHD和感染的新方法。肠道损伤通过传播促炎细胞因子环境，在放大全身性GVHD中起核心作用。分子靶向抑制激酶信号传导可能是一种有前景的治疗GVHD的方法，理想情况下是通过靶向多种细胞因子对免疫细胞和肠上皮细胞的冗余作用。在这篇综述中，我们讨论了关于胃肠道GVHD生物学、微生物群和代谢组与宿主的相互作用、潜在新靶器官的识别以及新型T细胞信号通路的识别和靶向的见解。因此，更好地理解GVHD生物学将为开发具有巨大临床益处的新型治疗策略铺平道路。
