title: Acute Graft-versus-Host Disease: Novel Biological Insights.
abstract: 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.
authors.affiliation: Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. Electronic address: teshima@med.hokudai.ac.jp.
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
mesh_terms: D000208:Acute Disease; D064591:Allografts; D016207:Cytokines / Q000276:immunology; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007410:Intestinal Diseases / Q000209:etiology / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D019879:Paneth Cells / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction / Q000276:immunology; D013272:Stomach Diseases / Q000209:etiology / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines
keywords: Butyrate; Graft-versus-host disease; Histone deacetylase; Intestinal stem cells; Janus kinase; Paneth cells; Ruxolitinib