{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:15:59Z","timestamp":1791292559330,"version":"4.1.0"},"reference-count":73,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2008,11,1]],"date-time":"2008-11-01T00:00:00Z","timestamp":1225497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Regulatory T cells (Treg) play a decisive role in many diseases including asthma and allergen-induced lung inflammation. However, little progress has been made developing new therapeutic strategies for pulmonary disorders. In the current study we demonstrate that cytokine:antibody complexes of IL-2 and anti-IL-2 mAb reduce the severity of allergen-induced inflammation in the lung by expanding Tregs in vivo. Unlike rIL-2 or anti-IL-2 mAb treatment alone, IL-2:anti-IL-2 complexes dampened airway inflammation and eosinophilia while suppressing IL-5 and eotaxin-1 production. Mucus production, airway hyperresponsiveness to methacholine, and parenchymal tissue inflammation were also dramatically reduced following IL-2:anti-IL-2 treatment. The suppression in allergic airway disease was associated with a marked expansion of Tregs (IL-10+CD4+CD25+ and Foxp3+CD4+CD25+) in the tissues, with a corresponding decrease in effector T cell responses. The ability of IL-2:anti-IL-2 complexes to suppress airway inflammation was dependent on Treg-derived IL-10, as IL-10+\/+, but not IL-10\u2212\/\u2212 Tregs, were capable of mediating the suppression. Furthermore, a therapeutic protocol using a model of established airway allergy highlighted the ability of IL-2:anti-IL-2 complexes to expand Tregs and prevent successive airway inflammation and airway hyperresponsiveness. This study suggests that endogenous Treg therapy may be a useful tool to combat the rising incidence of allergic airway disease.<\/jats:p>","DOI":"10.4049\/jimmunol.181.10.6942","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:00:36Z","timestamp":1397847636000},"page":"6942-6954","source":"Crossref","is-referenced-by-count":103,"title":["Suppression of Murine Allergic Airway Disease by IL-2:Anti-IL-2 Monoclonal Antibody-Induced Regulatory T Cells"],"prefix":"10.1093","volume":"181","author":[{"given":"Mark S.","family":"Wilson","sequence":"first","affiliation":[{"name":"Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"Pesce","sequence":"additional","affiliation":[{"name":"Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thirumalai R.","family":"Ramalingam","sequence":"additional","affiliation":[{"name":"Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert W.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Cheever","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute , Rockville, MD 20852"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Wynn","sequence":"additional","affiliation":[{"name":"Immunopathogensis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,11,15]]},"reference":[{"key":"2026012807070111900_R1","first-page":"R402","article-title":"Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-\u03b3","volume-title":"Arthritis Res. Ther.","year":"2005"},{"key":"2026012807070111900_R2","first-page":"3639","article-title":"Regulatory T cells in human autoimmune thyroid disease","volume-title":"J. Clin. Endocrinol. Metab.","year":"2006"},{"key":"2026012807070111900_R3","first-page":"1212","article-title":"CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells","volume-title":"J. Immunol.","year":"1998"},{"key":"2026012807070111900_R4","first-page":"271","article-title":"Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma","volume-title":"Nat. Rev. Immunol.","year":"2005"},{"key":"2026012807070111900_R5","first-page":"608","article-title":"Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease","volume-title":"Lancet","year":"2004"},{"key":"2026012807070111900_R6","first-page":"363","article-title":"Interleukin-10-secreting regulatory T cells in allergy and asthma","volume-title":"Curr. Allergy Asthma Rep.","year":"2006"},{"key":"2026012807070111900_R7","first-page":"627","article-title":"Role of regulatory T cells in allergy and asthma","volume-title":"Curr. Opin. Immunol.","year":"2003"},{"key":"2026012807070111900_R8","first-page":"269","article-title":"IL-10-producing type 1 regulatory T cells and allergy","volume-title":"Cell. Mol. Immunol.","year":"2007"},{"key":"2026012807070111900_R9","first-page":"8","article-title":"Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease","volume-title":"Immunol. Rev.","year":"2006"},{"key":"2026012807070111900_R10","first-page":"238","article-title":"The regulation of allergy and asthma","volume-title":"Immunol. Rev.","year":"2006"},{"key":"2026012807070111900_R11","first-page":"875","article-title":"Regulatory T cells and infection: a dangerous necessity","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012807070111900_R12","first-page":"1364","article-title":"Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season","volume-title":"Clin. Exp. Allergy","year":"2004"},{"key":"2026012807070111900_R13","first-page":"146","article-title":"Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients","volume-title":"J. Clin. Invest.","year":"2006"},{"key":"2026012807070111900_R14","first-page":"1209","article-title":"Induction of T \u201cregulatory\u201d cells by standardized house dust mite immunotherapy: an increase in CD4+ CD25+ interleukin-10+ T cells expressing peripheral tissue trafficking markers","volume-title":"Clin. Exp. Allergy","year":"2004"},{"key":"2026012807070111900_R15","first-page":"1255","article-title":"Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy","volume-title":"J. Allergy Clin. Immunol.","year":"2003"},{"key":"2026012807070111900_R16","first-page":"549","article-title":"Suppression of allergen reactive Th2 mediated responses and pulmonary eosinophilia by intranasal administration of an immunodominant peptide is linked to IL-10 production","volume-title":"Vaccine","year":"2003"},{"key":"2026012807070111900_R17","first-page":"1549","article-title":"CD4+CD25+ T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012807070111900_R18","first-page":"1199","article-title":"Suppression of allergic airway inflammation by helminth-induced regulatory T cells","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012807070111900_R19","first-page":"1539","article-title":"Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent","volume-title":"J. Exp. Med.","year":"2005"},{"key":"2026012807070111900_R20","first-page":"4848","article-title":"T regulatory cells 1 inhibit a Th2-specific response in vivo","volume-title":"J. Immunol.","year":"2000"},{"key":"2026012807070111900_R21","first-page":"5502","article-title":"Lung CD25 CD4 regulatory T cells suppress type 2 immune responses but not bronchial hyperreactivity","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012807070111900_R22","first-page":"3842","article-title":"CD4+CD25+ T cells regulate airway eosinophilic inflammation by modulating the Th2 cell phenotype","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012807070111900_R23","first-page":"2649","article-title":"Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells","volume-title":"J. Exp. Med.","year":"2006"},{"key":"2026012807070111900_R24","first-page":"1142","article-title":"A function for interleukin 2 in Foxp3-expressing regulatory T cells","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2026012807070111900_R25","first-page":"1152","article-title":"Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2026012807070111900_R26","first-page":"851","article-title":"Interleukin 2 signaling is required for CD4+ regulatory T cell function","volume-title":"J. Exp. Med.","year":"2002"},{"key":"2026012807070111900_R27","first-page":"167","article-title":"CD4 regulatory T cells prevent lethal autoimmunity in IL-2R\u03b2-deficient mice: implications for the nonredundant function of IL-2","volume-title":"Immunity","year":"2002"},{"key":"2026012807070111900_R28","first-page":"4850","article-title":"Homeostasis of peripheral CD4+ T cells: IL-2R \u03b1 and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers","volume-title":"J. Immunol.","year":"2002"},{"key":"2026012807070111900_R29","first-page":"3983","article-title":"IL-2, regulatory T cells, and tolerance","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012807070111900_R30","first-page":"253","article-title":"Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene","volume-title":"Cell","year":"1993"},{"key":"2026012807070111900_R31","first-page":"68","article-title":"Disruption of a new forkhead\/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse","volume-title":"Nat. Genet.","year":"2001"},{"key":"2026012807070111900_R32","first-page":"5115","article-title":"Selective availability of IL-2 is a major determinant controlling the production of CD4+CD25+Foxp3+ T regulatory cells","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012807070111900_R33","first-page":"665","article-title":"Tolerance, not immunity, crucially depends on IL-2","volume-title":"Nat. Rev. Immunol.","year":"2004"},{"key":"2026012807070111900_R34","first-page":"109","article-title":"The dichotomous role of IL-2: tolerance versus immunity","volume-title":"Trends Immunol.","year":"2006"},{"key":"2026012807070111900_R35","first-page":"1924","article-title":"Selective stimulation of T cell subsets with antibody-cytokine immune complexes","volume-title":"Science","year":"2006"},{"key":"2026012807070111900_R36","first-page":"941","article-title":"Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse","volume-title":"Immunity","year":"2006"},{"key":"2026012807070111900_R37","first-page":"235","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells","volume-title":"Nature","year":"2006"},{"key":"2026012807070111900_R38","first-page":"2941","article-title":"IL-13Ralpha2 and IL-10 coordinately suppress airway inflammation, airway-hyperreactivity, and fibrosis in mice","volume-title":"J. Clin. Invest.","year":"2007"},{"key":"2026012807070111900_R39","first-page":"766","article-title":"Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography","volume-title":"Am. J. Respir. Crit. Care Med.","year":"1997"},{"key":"2026012807070111900_R40","first-page":"1811","article-title":"Development of an assay to measure in vivo cytokine production in the mouse","volume-title":"Int. Immunol.","year":"1999"},{"key":"2026012807070111900_R41","first-page":"775","article-title":"Endogenous interleukin-10 suppresses allergen-induced airway inflammation and nonspecific airway responsiveness","volume-title":"Clin. Exp. Allergy","year":"2000"},{"key":"2026012807070111900_R42","first-page":"2644","article-title":"Interleukin-10 inhibits antigen-induced cellular recruitment into the airways of sensitized mice","volume-title":"J. Clin. Invest.","year":"1995"},{"key":"2026012807070111900_R43","first-page":"566","article-title":"The inhibitory cytokine IL-35 contributes to regulatory T-cell function","volume-title":"Nature","year":"2007"},{"key":"2026012807070111900_R44","first-page":"3021","article-title":"IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells","volume-title":"Eur. J. Immunol.","year":"2007"},{"key":"2026012807070111900_R45","first-page":"291","article-title":"Expansion of circulating Foxp3+CD25bright CD4+ T cells during specific venom immunotherapy","volume-title":"Clin. Exp. Allergy","year":"2008"},{"key":"2026012807070111900_R46","first-page":"780","article-title":"Mechanisms of allergen-specific immunotherapy","volume-title":"J. Allergy Clin. Immunol.","year":"2007"},{"key":"2026012807070111900_R47","first-page":"2139","article-title":"Glucocorticoid amplifies IL-2-dependent expansion of functional FoxP3+CD4+CD25+ T regulatory cells in vivo and enhances their capacity to suppress EAE","volume-title":"Eur. J. Immunol.","year":"2006"},{"key":"2026012807070111900_R48","first-page":"585","article-title":"Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012807070111900_R49","first-page":"2409","article-title":"IL-2 administration increases CD4+ CD25hi Foxp3+ regulatory T cells in cancer patients","volume-title":"Blood","year":"2006"},{"key":"2026012807070111900_R50","first-page":"7487","article-title":"Interleukin-2 administration alters the CD4+FOXP3+ T-cell pool and tumor trafficking in patients with ovarian carcinoma","volume-title":"Cancer Res.","year":"2007"},{"key":"2026012807070111900_R51","first-page":"1571","article-title":"IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo","volume-title":"Blood","year":"2006"},{"key":"2026012807070111900_R52","first-page":"120","article-title":"CD4+CD25+ T regulatory cells, immunotherapy of cancer, and interleukin-2","volume-title":"J. Immunother.","year":"2005"},{"key":"2026012807070111900_R53","first-page":"3192","article-title":"The IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity","volume-title":"Blood","year":"2007"},{"key":"2026012807070111900_R54","first-page":"582","article-title":"Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma","volume-title":"J. Immunother.","year":"2005"},{"key":"2026012807070111900_R55","first-page":"1238","article-title":"Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells","volume-title":"Nat. Med.","year":"2005"},{"key":"2026012807070111900_R56","first-page":"324","article-title":"IL-2 and IL-18 attenuation of airway hyperresponsiveness requires STAT4, IFN-\u03b3, and natural killer cells","volume-title":"Am. J. Respir. Cell Mol. Biol.","year":"2007"},{"key":"2026012807070111900_R57","first-page":"145","article-title":"IL-2 enhances allergic airway responses in rats by increased inflammation but not through increased synthesis of cysteinyl leukotrienes","volume-title":"J. Allergy Clin. Immunol.","year":"1999"},{"key":"2026012807070111900_R58","first-page":"1289","article-title":"Th2-driven, allergen-induced airway inflammation is reduced after treatment with anti-Tim-3 antibody in vivo","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012807070111900_R59","first-page":"546","article-title":"Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces","volume-title":"Immunity","year":"2008"},{"key":"2026012807070111900_R60","first-page":"1323","article-title":"Potential use of IL-2\/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease","volume-title":"Expert Opin. Biol. Ther.","year":"2006"},{"key":"2026012807070111900_R61","first-page":"1235","article-title":"Anti-cytokine antibodies as carrier proteins: prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes","volume-title":"J. Immunol.","year":"1993"},{"key":"2026012807070111900_R62","first-page":"44","article-title":"Cutting edge: mechanism of enhancement of in vivo cytokine effects by anti-cytokine monoclonal antibodies","volume-title":"J. Immunol.","year":"2008"},{"key":"2026012807070111900_R63","first-page":"1133","article-title":"Enhancement of the biologic effects of interleukin-3 in vivo by anti-interleukin-3 antibodies","volume-title":"Blood","year":"1993"},{"key":"2026012807070111900_R64","first-page":"917","article-title":"Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6 antibodies","volume-title":"Blood","year":"1995"},{"key":"2026012807070111900_R65","first-page":"1101","article-title":"Enhancement of the anti-tumor activity of recombinant interleukin-2 (rIL-2) by immunocomplexing with an F(ab\u2032)2 fragment of murine monoclonal antibody against rIL-2","volume-title":"Biol. Pharm. Bull.","year":"1994"},{"key":"2026012807070111900_R66","first-page":"535","article-title":"Pharmacokinetic alteration in rats of recombinant interleukin-2 (rIL-2) by immunocomplexing with a monoclonal antibody against rIL-2","volume-title":"Biol. Pharm. Bull.","year":"1994"},{"key":"2026012807070111900_R67","first-page":"3312","article-title":"IL-15-IgG2b fusion protein accelerates and enhances a Th2 but not a Th1 immune response in vivo, while IL-2-IgG2b fusion protein inhibits both","volume-title":"Eur. J. Immunol.","year":"1998"},{"key":"2026012807070111900_R68","first-page":"2865","article-title":"In vivo administration of purified human interleukin 2: II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant IL 2","volume-title":"J. Immunol.","year":"1985"},{"key":"2026012807070111900_R69","first-page":"2521","article-title":"PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs","volume-title":"J. Clin. Invest.","year":"2006"},{"key":"2026012807070111900_R70","first-page":"1787","article-title":"An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012807070111900_R71","first-page":"306","article-title":"IL-2 in vivo activities and antitumor efficacy enhanced by an anti-IL-2 mAb","volume-title":"J. Immunol.","year":"2006"},{"key":"2026012807070111900_R72","first-page":"1803","article-title":"Naive CD8+ T cells differentiate into protective memory-like cells after IL-2 anti IL-2 complex treatment in vivo","volume-title":"J. Exp. Med.","year":"2007"},{"key":"2026012807070111900_R73","first-page":"5118","article-title":"IL-2\/Anti-IL-2 antibody complex enhances vaccine-mediated antigen-specific CD8+ T cell responses and increases the ratio of effector\/memory CD8+ T cells to regulatory T cells","volume-title":"J. Immunol.","year":"2008"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/6942\/62580899\/8077.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/181\/10\/6942\/62580899\/8077.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:07:44Z","timestamp":1769602064000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/181\/10\/6942\/8007895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,11]]},"references-count":73,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2008,11,15]]},"published-print":{"date-parts":[[2008,11,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.181.10.6942","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2008,11]]},"published":{"date-parts":[[2008,11]]}}}