title: Targeting the IL17 pathway for the prevention of graft-versus-host disease.
abstract: Graft-versus-host disease (GVHD) is still a major complication of allogeneic stem cell transplantation (allo-SCT). The pathophysiology of GVHD is a multistep process initiated by tissue damage and proinflammatory cytokine cascades induced by the pretransplantation conditioning therapy. This eventually results in Th1-driven tissue damage. However, increasing evidence indicates the involvement of IL17-producing T cells in GVHD pathogenesis. Both CD4(+) and CD8(+) IL17-producing T cells are suspected of initiating the Th1 response and aggravating tissue inflammation, resulting in full-blown GVHD. In this review, we discuss the involvement of IL17-producing T cells in GVHD and the factors involved in their expansion, differentiation, and activation. Different dendritic cell (DC) subsets, such as plasmacytoid DCs and DC NK lectin group receptor 1(+) myeloid DCs have the capability to stimulate Th/Tc17 responses through the release of cytokines. Pivotal cytokines include IL1β, IL6, IL23, and TGFβ, which are known to drive differentiation and expansion of IL17-producing T cells, and these cytokines are highly elevated in patients after allo-SCT. Potent activators of these DC subsets are motifs that are released upon tissue damage and microbial exposure during allo-SCT. These motifs aggravate the Th/Tc17 response via the activation of various pathogen recognition receptors, thereby initiating and perpetuating GVHD. A more comprehensive understanding of the factors and DC subsets driving the IL17 pathway will result in developing and testing novel therapeutic approaches for the prevention of GVHD.
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anniek B
authors.initials: AB
authors.lastname: van der Waart
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Walter J F M
authors.initials: WJ
authors.lastname: van der Velden
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Blijlevens
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Harry.Dolstra@Radboudumc.nl.
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D020381:Interleukin-17
keywords: Allogeneic stem cell transplantation; Danger-associated molecular patterns (DAMP); Dendritic cell; GVHD; Interleukin 17; Pathogen-associated molecular patterns (PAMP); Th17 cell