title: GARP inhibits allergic airway inflammation in a humanized mouse model.
abstract: Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model.
  
  
  
  To analyze the therapeutic effects of sGARP, adult NOD/Scidγc(-/-) (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP.
  
  
  
  In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45(+) cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-β receptor pathway, mice additionally received anti-TGF-β receptor II (TGF-βRII) antibodies. Blocking the signaling of TGF-β through TGF-βRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation.
  
  
  
  Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases.
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Meyer-Martin
authors.affiliation: The Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: S A
authors.initials: SA
authors.lastname: Hahn
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Beckert
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Belz
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Heinz
authors.affiliation: The Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Jonuleit
authors.affiliation: The Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Becker
authors.affiliation: The Department of Pulmonology, University Medical Center, Leiden, Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Taube
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Korn
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Buhl
authors.affiliation: The III Medical Department, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Reuter
authors.affiliation: The Department of Dermatology, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Tuettenberg
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D018125:Receptors, Transforming Growth Factor beta; D007073:Immunoglobulin E; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: asthma; humanized animal model; pulmonary inflammation; regulatory T cells; tolerance