Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation.
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.
Department of Haematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Centre, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
Robert
R
Zeiser
Haematology Stem cell transplant Unit, Saint Louis Hospital, APHP, Paris, France.
Gerard
G
Socié
Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA. blaza001@umn.edu.
Bruce R
BR
Blazar
D000208:Acute Disease; D000818:Animals; D002470:Cell Survival / Q000276:immunology; D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D056747:Immunomodulation; D008213:Lymphocyte Activation / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors
D016207:Cytokines; D035683:MicroRNAs; D011948:Receptors, Antigen, T-Cell
danger associated molecular patterns; graft-versus-host disease; micro RNAs; neutrophils; novel targets