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Ferrata Storti Foundation
Haematologica 2020 Volume 105(11):2540-2549
New insights into the basic biology of acute graft-versus-host-disease
Alicia Li,1 Ciril Abraham,1 Ying Wang1,2 and Yi Zhang1,2
1Fels Institute for Cancer Research & Molecular Biology and 2Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
ABSTRACT
Although allogeneic hematopoietic stem cell transplantation is an important therapy for many hematologic and non-hematologic dis- eases, acute graft-versus-host disease (aGvHD) is a major obstacle to its success. The pathogenesis of aGvHD is divided into three distinct phases which occur largely as the result of interactions between infused donor T cells and numerous cell types of both hematopoietic and non-hematopoietic origin. In light of the disease’s immensely complex biology, epigenetics has emerged as a framework with which to examine aGvHD. This review focuses on new findings that clarify the roles that specific epigenetic regula- tors play in T-cell-mediated aGvHD development and discusses how their modulation could disrupt that process with beneficial effects. DNA methyl- transferases, histone methyltransferases and histone deacetylases are the most closely studied regulators across aGvHD priming, induction and effec- tor phases and have been manipulated using drugs and other methods in both murine models and clinical trials, with varying degrees of success. Antigen-presenting cells, effector T cells and memory T cells, among others, are targeted and affected by these regulators in different ways. Finally, our review highlights new directions for study and potential novel targets for modulation to abrogate aGvHD.
Introduction
The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is significantly hampered by acute graft-versus-host disease (aGvHD), which is caused by donor T cells that recognize and react to histocompatibility differences between the donor and host. It occurs in sequential priming, induction and effector phases (Figure 1).1 During priming, preparative irradiation and chemotherapeutic regimens for allo-HSCT can damage the patient’s tissues, leading to release of damage-asso- ciated molecular patterns (DAMP) and pathogen-associated molecular patterns (PAMP), as well as activation of host antigen-presenting cells (APC) such as dendrit- ic cells.1-6 Activated APC, including hematopoietic and non-hematopoietic cells, upregulate antigen-presenting molecules and costimulatory molecules to prime transplanted donor T cells.1-7 During induction, T-cell receptors on donor T cells react to alloantigens presented by host APC and undergo robust proliferation and differentiation into effector T cells that produce pro-inflammatory cytokines such as tumor necrosis factor (TNF)-a, interferon (IFN)-γ and interleukin (IL)-17.1 Upon persistent exposure to host alloantigens, most of these effector cells (~90%) under- go apoptotic contraction, but a proportion survive and become memory T cells.8-10 The final effector phase is characterized by infiltration of alloreactive effector cells into aGvHD target organs.1 Tissues already damaged by preparative treatments produce chemokines, recruiting T cells to their vicinity.1,11 The effector T cells rec- ognize and react to host alloantigens, mediating host tissue injury. The damaged host tissues recruit more alloreactive T cells and other types of inflammatory cells (e.g., monocytes/macrophages and granulocytes), leading to feed-forward amplifi- cation and continuation of aGvHD (Figure 1).1,2,4 Chronic GvHD may arise follow- ing or independently of aGvHD, but due to the conditions’ differing pathogeneses and clinical manifestations, chronic GvHD will not be discussed in this review.
Because aGvHD is T-cell-mediated, significant progress has been made in under- standing how alloreactive T cells are induced and sustained. APC may be primed
Correspondence:
YI ZHANG
yi.zhang@temple.edu
Received: April 30, 2020. Accepted: July 20, 2020. Pre-published: August 13, 2020.
doi:10.3324/haematol.2019.240291 ©2020 Ferrata Storti Foundation
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