{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:58:56Z","timestamp":1790863136405,"version":"4.1.0"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2013,3,11]],"date-time":"2013-03-11T00:00:00Z","timestamp":1362960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,3,11]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4\u2013immunoglobulin (CTLA-4\u2013Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4\u2013Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4\u2013Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA-4\u2013Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4\u2013Ig. Co-administration of CTLA-4\u2013Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4\u2013Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4\u2013Ig is independent of IDO expression. We show that CTLA-4\u2013Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4\u2013Ig is independent of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation.<\/jats:p>","DOI":"10.1111\/cei.12041","type":"journal-article","created":{"date-parts":[[2012,11,23]],"date-time":"2012-11-23T05:07:58Z","timestamp":1353647278000},"page":"113-120","source":"Crossref","is-referenced-by-count":17,"title":["Cytotoxic T lymphocyte antigen 4-immunoglobulin G is a potent adjuvant for experimental allergen immunotherapy"],"prefix":"10.1093","volume":"172","author":[{"given":"H","family":"Maazi","sequence":"first","affiliation":[{"name":"Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Shirinbak","sequence":"additional","affiliation":[{"name":"Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L E","family":"den Boef","sequence":"additional","affiliation":[{"name":"Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Fallarino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Volpi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M C","family":"Nawijn","sequence":"additional","affiliation":[{"name":"Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A J M","family":"van Oosterhout","sequence":"additional","affiliation":[{"name":"Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,3,11]]},"reference":[{"key":"2021122009533229700_cei12041-bib-0001","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.1398-9995.2009.02244.x","article-title":"Is the prevalence of asthma declining? Systematic review of epidemiological studies","volume":"65","author":"Anandan","year":"2010","journal-title":"Allergy"},{"key":"2021122009533229700_cei12041-bib-0002","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1056\/NEJMra054308","article-title":"The asthma epidemic","volume":"355","author":"Eder","year":"2006","journal-title":"N Engl J Med"},{"issue":"2 Suppl. 2","key":"2021122009533229700_cei12041-bib-0003","doi-asserted-by":"crossref","first-page":"S306","DOI":"10.1016\/j.jaci.2009.10.064","article-title":"Allergen immunotherapy","volume":"125","author":"Frew","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0004","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1157\/13101337","article-title":"Specific immunotherapy is effective in the prevention of new sensitivities","volume":"35","author":"Reha","year":"2007","journal-title":"Allergol Immunopathol (Madr)"},{"key":"2021122009533229700_cei12041-bib-0005","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1046\/j.1365-2222.2001.01161.x","article-title":"Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study","volume":"31","author":"Pajno","year":"2001","journal-title":"Clin Exp Allergy"},{"key":"2021122009533229700_cei12041-bib-0006","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1111\/j.1398-9995.2006.01068.x","article-title":"Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children","volume":"61","author":"Niggemann","year":"2006","journal-title":"Allergy"},{"key":"2021122009533229700_cei12041-bib-0007","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/0091-6749(94)90171-6","article-title":"The appropriate use of skin testing and allergen immunotherapy in young children","volume":"94","author":"Ownby","year":"1994","journal-title":"J Allergy Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0008","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.jaci.2004.04.017","article-title":"Status of immunotherapy: current and future","volume":"113","author":"Casale","year":"2004","journal-title":"J Allergy Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0009","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1097\/00130832-200412000-00012","article-title":"Adjuvants for allergen immunotherapy: experimental results and clinical perspectives","volume":"4","author":"Francis","year":"2004","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0010","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ni1178","article-title":"Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self","volume":"6","author":"Sakaguchi","year":"2005","journal-title":"Nat Immunol"},{"key":"2021122009533229700_cei12041-bib-0011","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/35105024","article-title":"T-cell regulation by CD28 and CTLA-4","volume":"1","author":"Alegre","year":"2001","journal-title":"Nat Rev Immunol"},{"key":"2021122009533229700_cei12041-bib-0012","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.4049\/jimmunol.165.3.1352","article-title":"CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression","volume":"165","author":"Carreno","year":"2000","journal-title":"J Immunol"},{"key":"2021122009533229700_cei12041-bib-0013","doi-asserted-by":"crossref","first-page":"149","DOI":"10.2174\/138161206775193046","article-title":"Mechanisms of CTLA-4-Ig in tolerance induction","volume":"12","author":"Alegre","year":"2006","journal-title":"Curr Pharm Des"},{"key":"2021122009533229700_cei12041-bib-0014","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1084\/jem.174.3.561","article-title":"CTLA-4 is a second receptor for the B cell activation antigen B7","volume":"174","author":"Linsley","year":"1991","journal-title":"J Exp Med"},{"key":"2021122009533229700_cei12041-bib-0015","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.2337\/db07-1712","article-title":"CD28\/CD154 blockade prevents autoimmune diabetes by inducing nondeletional tolerance after effector T-cell inhibition and regulatory T-cell expansion","volume":"57","author":"Rigby","year":"2008","journal-title":"Diabetes"},{"key":"2021122009533229700_cei12041-bib-0016","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.4049\/jimmunol.171.11.5673","article-title":"Cutting edge: transplantation tolerance through enhanced CTLA-4 expression","volume":"171","author":"Ariyan","year":"2003","journal-title":"J Immunol"},{"key":"2021122009533229700_cei12041-bib-0017","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1034\/j.1600-6143.2003.00127.x","article-title":"Long-term survival of intestinal allografts induced by costimulation blockade, busulfan and donor bone marrow infusion","volume":"3","author":"Guo","year":"2003","journal-title":"Am J Transplant"},{"key":"2021122009533229700_cei12041-bib-0018","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/s10875-011-9527-5","article-title":"CTLA-4-Ig therapy diminishes the frequency but enhances the function of treg cells in patients with rheumatoid arthritis","volume":"31","author":"Alvarez-Quiroga","year":"2011","journal-title":"J Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0019","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1016\/j.transproceed.2010.08.037","article-title":"High levels of IDO-expressing CD16+ peripheral cells, and Tregs in graft biopsies from kidney transplant recipients under belatacept treatment","volume":"42","author":"Furuzawa-Carballeda","year":"2010","journal-title":"Transplant Proc"},{"key":"2021122009533229700_cei12041-bib-0020","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/j.1365-2222.2004.01847.x","article-title":"Role of T cell co-stimulation in murine models of allergic asthma","volume":"34","author":"Deurloo","year":"2004","journal-title":"Clin Exp Allergy"},{"key":"2021122009533229700_cei12041-bib-0021","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nri1131","article-title":"Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling","volume":"3","author":"Rudd","year":"2003","journal-title":"Nat Rev Immunol"},{"key":"2021122009533229700_cei12041-bib-0022","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/nri2163","article-title":"IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation","volume":"7","author":"Puccetti","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"2021122009533229700_cei12041-bib-0023","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1016\/j.jaci.2007.11.021","article-title":"Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model","volume":"121","author":"Taher","year":"2008","journal-title":"J Allergy Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0024","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1111\/j.1398-9995.2010.02430.x","article-title":"Early markers for protective mechanisms during rush venom immunotherapy","volume":"65","author":"Bussmann","year":"2010","journal-title":"Allergy"},{"key":"2021122009533229700_cei12041-bib-0025","doi-asserted-by":"crossref","first-page":"5211","DOI":"10.4049\/jimmunol.180.8.5211","article-title":"1Alpha,25-dihydroxyvitamin D3 potentiates the beneficial effects of allergen immunotherapy in a mouse model of allergic asthma: role for IL-10 and TGF-beta","volume":"180","author":"Taher","year":"2008","journal-title":"J Immunol"},{"key":"2021122009533229700_cei12041-bib-0026","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1165\/ajrcmb.25.6.4607","article-title":"CTLA4-IgG reverses asthma manifestations in a mild but not in a more \u2018severe\u2019 ongoing murine model","volume":"25","author":"Deurloo","year":"2001","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2021122009533229700_cei12041-bib-0027","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1038\/nm1563","article-title":"Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy","volume":"13","author":"Grohmann","year":"2007","journal-title":"Nat Med"},{"key":"2021122009533229700_cei12041-bib-0028","doi-asserted-by":"crossref","first-page":"3857","DOI":"10.4049\/jimmunol.0903909","article-title":"Suppression of Th2-driven airway inflammation by allergen immunotherapy is independent of B cell and Ig responses in mice","volume":"185","author":"Shirinbak","year":"2010","journal-title":"J Immunol"},{"key":"2021122009533229700_cei12041-bib-0029","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.jim.2004.03.004","article-title":"A rapid flow cytometric method for determining the cellular composition of bronchoalveolar lavage fluid cells in mouse models of asthma","volume":"288","author":"van Rijt","year":"2004","journal-title":"J Immunol Methods"},{"key":"2021122009533229700_cei12041-bib-0030","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/j.1365-2249.2011.04448.x","article-title":"Iron administration reduces airway hyperreactivity and eosinophilia in a mouse model of allergic asthma","volume":"166","author":"Maazi","year":"2011","journal-title":"Clin Exp Immunol"},{"key":"2021122009533229700_cei12041-bib-0031","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1038\/ni846","article-title":"CTLA-4-Ig regulates tryptophan catabolism in vivo","volume":"3","author":"Grohmann","year":"2002","journal-title":"Nat Immunol"},{"key":"2021122009533229700_cei12041-bib-0032","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1084\/jem.20040942","article-title":"CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice","volume":"200","author":"Fallarino","year":"2004","journal-title":"J Exp Med"},{"key":"2021122009533229700_cei12041-bib-0033","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.clim.2007.08.019","article-title":"Abatacept modulates human dendritic cell-stimulated T-cell proliferation and effector function independent of IDO induction","volume":"126","author":"Davis","year":"2008","journal-title":"Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0034","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1126\/science.1160062","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume":"322","author":"Wing","year":"2008","journal-title":"Science"},{"key":"2021122009533229700_cei12041-bib-0035","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1165\/ajrcmb.19.4.3112m","article-title":"Allergen immunotherapy inhibits airway eosinophilia and hyperresponsiveness associated with decreased IL-4 production by lymphocytes in a murine model of allergic asthma","volume":"19","author":"Van Oosterhout","year":"1998","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2021122009533229700_cei12041-bib-0036","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1038\/nri1488","article-title":"Forkhead-box transcription factors and their role in the immune system","volume":"4","author":"Coffer","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"2021122009533229700_cei12041-bib-0037","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1097\/01.tp.0000285293.75911.56","article-title":"Nitric oxide and indoleamine 2,3-dioxygenase mediate CTLA4Ig-induced survival in heart allografts in rats","volume":"84","author":"Hill","year":"2007","journal-title":"Transplantation"},{"key":"2021122009533229700_cei12041-bib-0038","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1084\/jem.192.9.1213","article-title":"Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells","volume":"192","author":"Jonuleit","year":"2000","journal-title":"J Exp Med"},{"key":"2021122009533229700_cei12041-bib-0039","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.jaci.2010.11.025","article-title":"Wasp venom immunotherapy induces activation and homing of CD4(+)CD25(+) forkhead box protein 3-positive regulatory T cells controlling T(H)1 responses","volume":"127","author":"Kerstan","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"2021122009533229700_cei12041-bib-0040","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/intimm\/dxp095","article-title":"Regulatory T cells: how do they suppress immune responses?","volume":"21","author":"Sakaguchi","year":"2009","journal-title":"Int Immunol"},{"key":"2021122009533229700_cei12041-bib-0041","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1600-065X.2009.00780.x","article-title":"The clinical utility of inhibiting CD28-mediated costimulation","volume":"229","author":"Linsley","year":"2009","journal-title":"Immunol Rev"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.12041","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/172\/1\/113\/41788086\/cei12041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/172\/1\/113\/41788086\/cei12041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T16:19:12Z","timestamp":1641053952000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/172\/1\/113\/6421015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,3,11]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2013,3,11]]},"published-print":{"date-parts":[[2013,3,11]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.12041","relation":{},"ISSN":["1365-2249","0009-9104"],"issn-type":[{"value":"1365-2249","type":"electronic"},{"value":"0009-9104","type":"print"}],"subject":[],"published-other":{"date-parts":[[2013,4]]},"published":{"date-parts":[[2013,3,11]]}}}