title: TLR-2 activation induces regulatory T cells and long-term suppression of asthma manifestations in mice.
abstract: Asthma is a chronic inflammatory disease of the airways characterized by variable airway obstruction and airway hyperresponsiveness (AHR). The T regulatory (Treg) cell subset is critically important for the regulation of immune responses. Adoptive transfer of Treg cells has been shown to be sufficient for the suppression of airway inflammation in experimental allergic asthma. Intervention strategies aimed at expanding the Treg cell population locally in the airways of sensitized individuals are therefore of high interest as a potential therapeutic treatment for allergic airway disease. Here, we aim to test whether long-term suppression of asthma manifestations can be achieved by locally expanding the Treg cell subset via intranasal administration of a TLR-2 agonist. To model therapeutic intervention aimed at expanding the endogenous Treg population in a sensitized host, we challenged OVA-sensitized mice by OVA inhalation with concomitant intranasal instillation of the TLR-2 agonist Pam3Cys, followed by an additional series of OVA challenges. Pam3Cys treatment induced an acute but transient aggravation of asthma manifestations, followed by a reduction or loss of AHR to methacholine, depending on the time between Pam3Cys treatment and OVA challenges. In addition, Pam3Cys-treatment induced significant reductions of eosinophils and increased numbers of Treg cells in the lung infiltrates. Our data show that, despite having adverse acute effects, TLR2 agonist treatment as a therapeutic intervention induces an expansion of the Treg cell population in the lungs and results in long-term protection against manifestation of allergic asthma upon subsequent allergen provocation. Our data indicate that local expansion of Tregs in allergic airway disease is an interesting therapeutic approach that warrants further investigation.
authors: Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University of Groningen, GRIAC Research Institute, University Medical Centre Groningen-UMCG, Groningen, The Netherlands. m.c.nawijn@umcg.nl
authors: Martijn C
authors: MC
authors: Nawijn
authors: Alexandre C
authors: AC
authors: Motta
authors: Renée
authors: R
authors: Gras
authors: Soheila
authors: S
authors: Shirinbak
authors: Hadi
authors: H
authors: Maazi
authors: Antoon J M
authors: AJ
authors: van Oosterhout
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007073:Immunoglobulin E / Q000378:metabolism; D008074:Lipoproteins / Q000819:agonists / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D008074:Lipoproteins; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016210:Methacholine Chloride; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D007073:Immunoglobulin E
references: Am J Respir Cell Mol Biol. 2007 Jul;37(1):85-96
references: 17332440
references: Am J Physiol Lung Cell Mol Physiol. 2009 Mar;296(3):L307-19
references: 19028981
references: Proc Natl Acad Sci U S A. 2006 May 2;103(18):7048-53
references: 16632602
references: J Immunol. 2005 Jun 15;174(12):7558-63
references: 15944255
references: Allergy. 2009 Mar;64(3):335-47
references: 19220222
references: Respir Res. 2008 Apr 01;9:30
references: 18380907
references: J Immunol. 2008 Oct 15;181(8):5396-404
references: 18832696
references: J Immunol. 2008 May 1;180(9):5862-70
references: 18424705
references: J Immunol. 2003 Nov 15;171(10):4984-9
references: 14607893
references: Science. 2005 Aug 26;309(5739):1380-4
references: 16123302
references: J Exp Med. 2006 Dec 25;203(13):2853-63
references: 17178920
references: Vaccine. 2005 Sep 15;23(39):4721-6
references: 15964669
references: J Immunol. 2004 Apr 15;172(8):4733-43
references: 15067049
references: J Exp Med. 2005 Dec 5;202(11):1549-61
references: 16314437
references: J Immunol. 2010 Oct 1;185(7):3857-65
references: 20802147
references: Am J Respir Cell Mol Biol. 2011 Aug;45(2):295-303
references: 20971879
references: Immunology. 2007 Oct;122(2):149-56
references: 17848162
references: Curr Opin Allergy Clin Immunol. 2007 Dec;7(6):535-41
references: 17989531
references: J Immunol. 2009 Oct 1;183(7):4458-66
references: 19748987
references: J Biol Chem. 1999 Nov 19;274(47):33419-25
references: 10559223
references: J Immunol. 2005 Dec 15;175(12):8051-9
references: 16339542
references: PLoS One. 2012;7(10):e47102
references: 23071726
references: Clin Exp Allergy. 2009 Sep;39(9):1415-26
references: 19624523
references: Am J Respir Cell Mol Biol. 2004 Aug;31(2):241-5
references: 15044215
references: Nat Immunol. 2004 Oct;5(10):987-95
references: 15454922
references: Am J Respir Cell Mol Biol. 2008 Jan;38(1):26-31
references: 17690330
references: Pediatr Pulmonol. 2008 Jan;43(1):11-9
references: 18041080
references: Am J Respir Cell Mol Biol. 2004 Jun;30(6):777-83
references: 14656745
references: Trends Immunol. 2006 Aug;27(8):387-93
references: 16814607
references: J Allergy Clin Immunol. 2008 Sep;122(3):617-24.e6
references: 18672278
references: Clin Exp Allergy. 2012 Oct;42(10):1519-28
references: 22994349
references: J Occup Med Toxicol. 2008 Feb 27;3 Suppl 1:S5
references: 18315836
references: Clin Exp Allergy. 2010 Apr;40(4):524-7
references: 20447072
references: Respir Res. 2009 Oct 07;10:93
references: 19811658
references: Cell Host Microbe. 2009 Jan 22;5(1):47-58
references: 19154987
references: J Exp Med. 2003 Feb 17;197(4):403-11
references: 12591899
references: J Immunol. 2004 Mar 1;172(5):2739-43
references: 14978071
references: J Immunol. 2004 Mar 15;172(6):3842-9
references: 15004191
references: Am J Respir Cell Mol Biol. 2008 Mar;38(3):263-8
references: 18079492
references: J Clin Invest. 2006 Feb;116(2):485-94
references: 16424940