Advances in understanding the pathogenesis of graft‐versus‐host disease

Abstract

Summary Acute graft‐versus‐host disease (GVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). The emergence of different immuno‐prophylaxis strategies, such as post‐transplant cyclophosphamide or anti‐thymocyteglobulin has reduced the incidence of acute GVHD in recent years. The biology of the acute GVHD we observe in the clinic may change due to the use of novel immuno‐stimulatory agents, including immune checkpoint inhibitors or anti‐neoplastic immune‐modifiers, like lenalidomide, given before or after allo‐HSCT. Here we discuss the recent advances in our understanding of acute GVHD with a focus on early events of the disease, including tissue damaging factors, innate immune cells, costimulatory pathways, immune cell signalling, immuno‐regulatory cell types, biomarkers of GVHD and regenerative approaches. New insight in the pathogenesis of acute GVHD has revealed the role of pro‐inflammatory intracellular signalling, defects in intestinal tissue regeneration and anti‐bacterial defence, as well as a reduced diversity of the microbiome, which will be the basis for the development of novel therapies.

Tolerance to Bone Marrow Transplantation: Do Mesenchymal Stromal Cells Still Have a Future for Acute or Chronic GvHD?

“…Host dendritic cells (DCs), inflammatory monocytes and neutrophils migrate from the damaged intestinal epithelium towards mesenteric lymph nodes, where donor T cells are activated. Moreover, IFNa and IFNg can induce chemokines (CXCL9, CXCL10, and CXCL11) that recruit helper T cells 1 (Th1) and cytotoxic T cells 1 (Tc1) and NK cells, all expressing CXCR3 (5,(7)(8)(9)(10).…”

“…APCs also express inhibitory molecules that can down-modulate the immune response. Generally speaking, these "inhibitory" mechanisms can be viewed as the effort of the damaged tissue to repair and counteract the tissue damage, by inhibiting T cell responses and by the production and release of tissue repair factors such as keratinocyte growth factor (KGF) by fibroblasts, amphiregulin by Tregs, IL-22 by innate lymphoid cells type 3 and R spondin by fibroblasts (5,7,8).…”

“…As general comments about the clinical trials of MSCs for aGvHD, one can say that the pathogenesis of this disease involves many molecules, cells and pathways, which vary also according to the anatomical site involved as well as time during disease development, as described briefly above. Just to make matters even more complex, the same molecules can in some cases play opposite pro-and anti-inflammatory roles according to the disease status: one canonical example is IL-33 whose administration in animal models of GvHD may result in attenuation or exacerbation of the disease, according to the schedule at which it is administered (8). Furthermore, most clinical trials have been performed on groups of patients who had seen 3 and up to 6 different lines of therapy before receiving MSCs.…”

Extracellular Vesicles After Allogeneic Hematopoietic Cell Transplantation: Emerging Role in Post-Transplant Complications

“…The targeting of host cell death is mediated by the expression of Fas Ligand and by release of granzyme B and perforins (9). Another significant factor in aGvHD pathogenesis is the production of cytokines and chemokines [e.g., interleukin (IL)-1, interferon γ (IFN-γ), tumor necrosis factor (TNF), that can directly and indirectly exert cytotoxicity (10).…”

Acute Graft‐versus‐Host Disease: Emerging Insights and Updates into Detection, Prevention, and Treatment

“…Although it is recognized that several advances in the realm of pathophysiology have been made by others, discussion of this topic is outside the scope of this review. 20,21 Instead, this serves to highlight some of the recent advancements and updates made in standardization of scoring of GVHD, biomarker detection and utilization, and novel pharmacologic prevention and treatment strategies.…”