Pathogenesis of acute graft‐versus‐host disease: from intestinal microbiota alterations to donor T cell activation

Abstract

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication of allogeneic haematopoietic cell transplantation (allo-HCT). Here we discuss the aGVHD pathophysiology initiated by multiple signals that cause alloreactive T-cell activation. The outcome of such donor T-cell activation is influenced by T-cell receptor-signal strength, anatomical location, co-stimulatory/co-inhibitory signals and differentiation stage (naive, effector/memory) of T-cells. Additionally, cross-priming of T cells to antigens expressed by pathogens can contribute to aGVHD-mediated tissue injury. In addition to the properties of donor T-cell activation, highly specialized tissue resident cell types, such as innate lymphoid cells, antigen-presenting cells, immune regulatory cells and various intestinal cell populations are critically involved in aGVHD pathogenesis. The role of the thymus and secondary lymphoid tissue injury, non-haematopoietic cells, intestinal microflora, cytokines, chemokines, microRNAs, metabolites and kinases in aGVHD pathophysiology will be highlighted. Acute GVHD pathogenic mechanisms will be connected to novel therapeutic approaches under development for, and tested in, the clinic.

Acute graft-versus-host disease of the gut: considerations for the gastroenterologist

“…The immune-mediated destruction of the intestinal mucosa leads to a failure of fluid resorption, particularly in the ileum, and is largely responsible for voluminous diarrhoea in patients with acute GVHD 22,23 . In addition, the destruction of mucosal cells at the brush border and consequent reduction in luminal levels of disaccharidase enzymes creates an osmotic effect due to the passage of unabsorbed carbohydrates 22,23 . Dysbiosis depletes the gut of bacterial populations, which might otherwise mitigate this effect via metabolism of these luminal polysaccharides 23 .…”

“…In addition, the destruction of mucosal cells at the brush border and consequent reduction in luminal levels of disaccharidase enzymes creates an osmotic effect due to the passage of unabsorbed carbohydrates 22,23 . Dysbiosis depletes the gut of bacterial populations, which might otherwise mitigate this effect via metabolism of these luminal polysaccharides 23 . Furthermore, compromise of brush border tight junctions (also known as zonulae occludentes) in the setting of a vigorous inflammatory response can lead to substantial mucosal protein loss, therefore drawing fluid into the intestinal lumen via oncotic pressure 24 .…”

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

“…8, [17][18][19][20] In HLA-matched sibling HCT, T-cell alloreactivity is directed against mHAgs, that is, polymorphic non-self-peptides encoded anywhere in the human genome. 9,[11][12][13] Allorecognition of mHAgs is mediated by conventional self-HLA-restricted, foreign peptide-specific T cells whose repertoire is shaped by positive and negative selection in the thymus.…”

Interleukin-6 in Allogeneic Stem Cell Transplantation: Its Possible Importance for Immunoregulation and As a Therapeutic Target

“…Graft-versus-host disease is a complex biological process, which includes severe immune dysregulation with sustained inflammation (4). Several studies have identified interleukin-6 (IL-6) and as an important factor in the pathophysiology of GVHD (5, 6).…”