title: Rat acute GvHD is Th1 driven and characterized by predominant donor CD4+T-cell infiltration of skin and gut.
abstract: Acute graft-versus-host disease (aGvHD) remains a significant hurdle to successful treatment of many hematological disorders. The disease is caused by infiltration of alloactivated donor T cells primarily into the gastrointestinal tract and skin. Although cytotoxic T cells mediate direct cellular damage, T helper (Th) cells differentially secrete immunoregulatory cytokines. aGvHD is thought to be initiated primarily by Th1 cells but a consensus is still lacking regarding the role of Th2 and Th17 cells. The aim of this study was to determine the contribution of distinct T-cell subsets to aGvHD in the rat. aGvHD was induced by transplanting irradiated rats with T-cell-depleted major histocompatibility complex-mismatched bone marrow, followed 2 weeks later by donor lymphocyte infusion. Near complete donor T-cell chimerism was achieved in the blood and lymphatic tissues, in contrast to mixed chimerism in the skin and gut. Skin and gut donor T cells were predominantly CD4+, in contrast to T cells in the blood and lymphatic tissues. Genes associated with Th1 cells were upregulated in gut, liver, lung, and skin tissues affected by aGvHD. Increased serum levels of CXCL10 and IL-18 preceded symptoms of aGvHD, accompanied by increased responsiveness to CXCL10 by blood CD4+T cells. No changes in the expression of Th2- or Th17-associated genes were observed, indicating that aGvHD in this rat model is mainly Th1 driven. The rat model of aGvHD could be instrumental for further investigations of donor T-cell subsets in the skin and gut and for exploring therapeutic options to ameliorate symptoms of aGvHD.
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
authors.forename: Margherita
authors.initials: M
authors.lastname: Boieri
authors.affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Pranali
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Dasaradha
authors.initials: D
authors.lastname: Jalapothu
authors.affiliation: Primate Genetics Laboratory, German Primate Center, Göttingen, Germany.
authors.forename: Olena
authors.initials: O
authors.lastname: Zaitseva
authors.affiliation: Primate Genetics Laboratory, German Primate Center, Göttingen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Walter
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Bent
authors.initials: B
authors.lastname: Rolstad
authors.affiliation: Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
authors.forename: Christian
authors.initials: C
authors.lastname: Naper
authors.affiliation: Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital - Rikshospitalet, Oslo, Norway. Electronic address: marit.inngjerdingen@rr-research.no.
authors.forename: Marit
authors.initials: M
authors.lastname: Inngjerdingen
mesh_terms: D000208:Acute Disease; D000818:Animals; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D006086:Graft vs Host Disease / Q000209:etiology* / Q000473:pathology; D006239:Haplotypes; D006649:Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008297:Male; D010641:Phenotype; D051381:Rats; D012867:Skin / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014019:Tissue Donors
chemical_list: D015415:Biomarkers; D006649:Histocompatibility Antigens