title: Chronic graft-versus-host-disease in CD34(+)-humanized NSG mice is associated with human susceptibility HLA haplotypes for autoimmune disease.
abstract: Chronic graft-versus-host disease (cGVHD) is a significant hurdle to long-term hematopoietic stem-cell transplantation success. Insights into the pathogenesis and mechanistical investigations of novel therapeutic strategies are limited as appropriate animal models are missing. The immunodeficient NSG mouse - when humanized with human bone marrow, fetal liver and thymus (BLT NSG) - is prone for cGVHD, yet mainly affects the skin. In contrast, the NSG mouse humanized exclusively with CD34(+)-selected, CD3(+)-depleted stem cells (CD34(+)NSG) has neither been described for acute nor chronic GVHD so far. This is the first report about the development of systemic autoimmune cGVHD ≥24 weeks post stem cell receipt involving lung, liver, skin, gingiva and intestine in two NSG cohorts humanized with CD34(+) grafts from different donors. Affected mice presented with sclerodermatous skin, fibrotic lung, severe hepatitis, and massive dental malformation/loss. CD4(+)-dominated, TH2-biased, bulky T-cell infiltrates featured highly skewed T cell receptor (TCR) repertoires, clonal expansions, and autoreactive TCRs. In affected tissues profibrotic IL-13 and -4 dominated over TH1 cytokines IFN-γ and TNF-α. Thus, the time point of manifestation and the phenotype match human systemic pleiotropic sclerodermatous GVHD. The CD34(+)NSG-model's intrinsic deficiency of thymus, thymus-derived regulatory T cells (nTreg) and B cells emphasizes the role of the genetic polymorphism and the cytokines in the pathogenesis of cGVHD. Importantly, the only factor discriminating diseased versus non-diseased CD34(+)NSG cohorts were two risk HLA haplotypes that in human mediate susceptibility for autoimmune disease (psoriasis). Thus, the CD34(+)NSG model may serve as a platform for addressing issues related to the pathophysiology and treatment of human autoimmunity and chronic GVHD.
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Sonntag
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany; Department of Radiation Oncology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Eckert
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Welker
authors.affiliation: Institute of Pathology, Eberhard Karls University Tübingen, Liebermeisterstraße 8, 72076 Tübingen, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Müller
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Müller
authors.affiliation: Department of Radiation Oncology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.affiliation: Institute of Pathology, Eberhard Karls University Tübingen, Liebermeisterstraße 8, 72076 Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Laboratory for Immunopathology, Eberhard Karls University Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Klein
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Blank
authors.affiliation: Pediatric Hematology, Oncology and Stem Cell Transplantation Dr. von Hauner'sches Kinderspital, Ludwig-Maximilian-University Munich, Lindwurmstraße 4, 80337 München, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Feuchtinger
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schumm
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.affiliation: Department of General Pediatrics, Oncology/Hematology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 1, 72076 Tübingen, Germany. Electronic address: karin.schilbach@med.uni-tuebingen.de.
authors.forename: Karin
authors.initials: K
authors.lastname: Schilbach
mesh_terms: D000483:Alleles; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016130:Immunophenotyping; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D051379:Mice; D010641:Phenotype
chemical_list: D016207:Cytokines; D006680:HLA Antigens
keywords: Autoimmunity; Chronic graft-versus-host disease; Extended HLA haplotypes; Humanized mouse; T-cell-receptor repertoire; cGVHD model; cGVHD pathology