{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:10:53Z","timestamp":1779912653599,"version":"3.53.1"},"reference-count":120,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T00:00:00Z","timestamp":1525305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>There are similarities between the immune response following immunization with aluminum adjuvants and the immune response elicited by some helminthic parasites, including stimulation of immunoglobulin E (IgE) and eosinophilia. Immunization with aluminum adjuvants, as with helminth infection, induces a Th2 type cell mediated immune response, including eosinophilia, but does not induce an environment conducive to the induction of regulatory mechanisms. Helminths play a role in what is known as the hygiene hypothesis, which proposes that decreased exposure to microbes during a critical time in early life has resulted in the increased prevalence and morbidity of asthma and atopic disorders over the past few decades, especially in Western countries. In addition, gut and lung microbiome composition and their interaction with the immune system plays an important role in a properly regulated immune system. Disturbances in microbiome composition are a risk factor for asthma and allergies. We propose that immunization with aluminum adjuvants in general is not favorable for induction of regulatory mechanisms and, in the context of the hygiene hypothesis and microbiome theory, can be viewed as an amplifying factor and significant contributing risk factor for allergic diseases, especially in a genetically susceptible subpopulation.<\/jats:p>","DOI":"10.3390\/ijerph15050901","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T03:20:27Z","timestamp":1525317627000},"page":"901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Aluminum Adjuvant-Containing Vaccines in the Context of the Hygiene Hypothesis: A Risk Factor for Eosinophilia and Allergy in a Genetically Susceptible Subpopulation?"],"prefix":"10.3390","volume":"15","author":[{"given":"Todd D.","family":"Terhune","sequence":"first","affiliation":[{"name":"College of Pharmacy, Department of Pharmaceutical Sciences, Nova Southeastern University, 1382 Terry Bldg, 3200 South University Drive, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Deth","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Department of Pharmaceutical Sciences, Nova Southeastern University, 1382 Terry Bldg, 3200 South University Drive, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Global Advisory Committee on Vaccine Safety (GACVS) (2009). WHO secretariat. Global safety of vaccines: Strengthening systems for monitoring, management and the role of GACVS. Expert Rev. Vaccines, 8, 705\u2013716.","DOI":"10.1586\/erv.09.40"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1586\/erv.09.107","article-title":"Update on vaccination guidelines for allergic children","volume":"8","author":"Kelso","year":"2009","journal-title":"Expert Rev. Vaccines"},{"key":"ref_3","unstructured":"Centers for Disease Control and Prevention (2017, April 14). Recommended Immunization Schedules for Persons Aged 0 Through 18 Years, USA, 2016, Available online: http:\/\/www.cdc.gov\/vaccines\/schedules\/downloads\/child\/0-18yrs-child-combined-schedule.pdf."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"C623","DOI":"10.1152\/ajpcell.1998.275.3.C623","article-title":"The mechanism of IL-5 signal transduction","volume":"275","author":"Adachi","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.coi.2008.04.001","article-title":"IL-5 and eosinophilia","volume":"20","author":"Takatsu","year":"2008","journal-title":"Curr. Opin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1146\/annurev.immunol.24.021605.090720","article-title":"The eosinophil","volume":"24","author":"Rothenberg","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1159\/000097357","article-title":"Role of cytokines in allergic inflammation","volume":"142","author":"Nakajima","year":"2007","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3643","DOI":"10.3748\/wjg.v10.i24.3643","article-title":"Interleukin (IL) 5 levels and eosinophilia in patients with intestinal parasitic diseases","volume":"10","author":"Ustun","year":"2004","journal-title":"World J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/S0022-3476(05)80592-X","article-title":"Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection","volume":"120","author":"Garofalo","year":"1992","journal-title":"J. Pediatr."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/rr41","article-title":"Th2 cytokines and asthma, the role of interleukin-5 in allergic eosinophilic disease","volume":"2","author":"Greenfeder","year":"2001","journal-title":"Respir. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.4049\/jimmunol.163.12.6448","article-title":"Aluminum Hydroxide Adjuvant Initiates Strong Antigen-Specific Th2 Responses in Absence of IL-4- or IL-13-Mediated Signaling","volume":"163","author":"Brewer","year":"1999","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4575","DOI":"10.1016\/j.vaccine.2007.03.045","article-title":"Activation of dendritic cells and induction of CD4+ T cell differentiation by aluminum-containing adjuvants","volume":"25","author":"Sokolovska","year":"2007","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4403","DOI":"10.4049\/jimmunol.0900164","article-title":"Alum Induces Innate Immune Responses through Macrophage and Mast Cell Sensors, but These Sensors Are Not Required for Alum to Act as an Adjuvant for Specific Immunity","volume":"183","author":"Mckee","year":"2009","journal-title":"J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.vaccine.2012.11.044","article-title":"Disparate adjuvant properties among three formulations of \u201calum\u201d","volume":"31","author":"Cain","year":"2013","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13146","DOI":"10.1038\/srep13146","article-title":"IL-33 released by alum is responsible for early cytokine production and has adjuvant properties","volume":"5","author":"Rose","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1084\/jem.183.1.195","article-title":"Interleukin 5 Deficiency Abolishes Eosinophilia, Airways Hyperreactivity, and Lung Damage in a Mouse Asthma Model","volume":"183","author":"Foster","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_17","unstructured":"Ada, G.L. (1994). The selective induction of different immune responses by vaccine adjuvants. Strategies in Vaccine Design, R.G. Lands Company."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1093\/intimm\/dxn025","article-title":"Gr1+IL-4 producing innate cells are induced in response to Th2 stimuli and suppress Th1-dependent antibody responses","volume":"20","author":"Mckee","year":"2008","journal-title":"Int. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3181\/00379727-156-39951","article-title":"Eosinophil Response to Alum Adjuvants. Involvement of T Cells in Non-Antigen-Dependent Mechanisms","volume":"156","author":"Walls","year":"1977","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_20","unstructured":"Liesveld, J., and Reagan, P. (2017, April 24). Eosinophilia. Merck Manual 2014. Available online: http:\/\/www.merckmanuals.com\/professional\/hematology-and-oncology\/eosinophilic-disorders\/eosinophilia."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1093\/intimm\/dxp102","article-title":"IL-5- and eosinophil-meditated inflammation: From discovery to therapy","volume":"21","author":"Kouro","year":"2009","journal-title":"Int. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/S0091-6749(97)70029-0","article-title":"Upregulation of alpha GM-CSF-receptor in nonatopic asthma but not in atopic asthma","volume":"99","author":"Kotsimbos","year":"1997","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1164\/ajrccm.162.6.9912001","article-title":"Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group","volume":"162","author":"Amin","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1365-2230.1990.tb02086.x","article-title":"Blood eosinophilia in atopic dermatitis","volume":"15","author":"Uehara","year":"1990","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1034\/j.1399-3038.2003.00061.x","article-title":"Allergen-induced cytokine secretion in atopic and non-atopic asthmatic children","volume":"14","author":"Mai","year":"2003","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1016\/j.rmed.2015.04.004","article-title":"IL-5, IL-8 and MMP -9 levels in exhaled breath condensate of atopic and nonatopic asthmatic children","volume":"109","author":"Turkeli","year":"2015","journal-title":"Respir. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1442-200x.2004.02004.x","article-title":"Expansion of activated eosinophils in infants with severe atopic dermatitis","volume":"47","author":"Toma","year":"2005","journal-title":"Pediatr. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/j.1365-2567.2004.01925.x","article-title":"The increased prevalence of allergy and the hygiene hypothesis: Missing immune deviation, reduced immune suppression, or both?","volume":"112","author":"Romagnani","year":"2004","journal-title":"Immunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13223-015-0102-0","article-title":"The human microbiome, asthma, and allergy","volume":"11","author":"Riiser","year":"2015","journal-title":"Allergy Asthma Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.immuni.2011.03.015","article-title":"An Unexpected Role for Uric Acid as an Inducer of T Helper 2 Cell Immunity to Inhaled Antigens and Inflammatory Mediator of Allergic Asthma","volume":"34","author":"Kool","year":"2011","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S1074-7613(00)80294-0","article-title":"IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses","volume":"4","author":"Kopf","year":"1996","journal-title":"Immunity"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1126\/science.1089926","article-title":"Promotion of B cell immune responses via an alum-induced myeloid cell population","volume":"304","author":"Jordan","year":"2004","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/eji.201141953","article-title":"Immunization induces activation of bone marrow eosinophils required for plasma cell survival","volume":"42","author":"Chu","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1600-065X.2011.01026.x","article-title":"Eosinophils: Multifaceted biological properties and roles in health and disease","volume":"242","author":"Kita","year":"2011","journal-title":"Immunol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3548","DOI":"10.4049\/jimmunol.1302241","article-title":"Eosinophils Regulate Peripheral B Cell Numbers in Both Mice and Humans","volume":"192","author":"Wong","year":"2014","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wong, T.W., Kita, H., Hanson, C.A., Walters, D.K., Arendt, B.K., and Jelinek, D.F. (2013). Induction of malignant plasma cell proliferation by eosinophils. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070554"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1084\/jem.184.5.1871","article-title":"Schistosoma mansoni egg induced early IL-4 production is dependent upon IL-5 and eosinophils","volume":"184","author":"Sabin","year":"1996","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/j.0105-2896.2004.00176.x","article-title":"Immunopathogenesis of schistosomiasis","volume":"201","author":"Wynn","year":"2004","journal-title":"Immunol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1002\/eji.201242372","article-title":"The vaccine adjuvant alum inhibits IL-12 by promoting PI3 kinase signaling while chitosan does not inhibit IL-12 and enhances Th1 and Th17 responses","volume":"42","author":"Mori","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1097\/00008480-199810060-00010","article-title":"Searching for the cause of the increase in asthma","volume":"10","author":"Crater","year":"1998","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1136\/bmj.299.6710.1259","article-title":"Hay fever, hygiene, and household size","volume":"299","author":"Strachan","year":"1989","journal-title":"Br. Med. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1111\/j.1365-2222.1987.tb02004.x","article-title":"Allergic reactivity and socio-economic level in a tropical environment","volume":"17","author":"Lynch","year":"1987","journal-title":"Clin. Allergy"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1159\/000236521","article-title":"Allergic reactivity of children of different socioeconomic levels in tropical populations","volume":"101","author":"Hagel","year":"1993","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/S1471-4906(01)01958-5","article-title":"Th2 responses without atopy: Immunoregulation in chronic helminth infections and reduced allergic disease","volume":"22","author":"Yazdanbakhsh","year":"2001","journal-title":"Trends Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1046\/j.1365-2249.2002.01908.x","article-title":"Can intestinal helminth infections (geohelminths) affect the development and expression of asthma and allergic disease?","volume":"128","author":"Cooper","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0035-9203(64)90068-9","article-title":"Mild prolonged schistosomiasis in mice: Alterations in host response with time and the development of portal fibrosis","volume":"58","author":"Andrade","year":"1964","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.4049\/jimmunol.114.5.1437","article-title":"Spontaneous modulation of granulomatous hypersensitivity in Schistosomiasis mansoni","volume":"114","author":"Boros","year":"1975","journal-title":"J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"150","DOI":"10.4049\/jimmunol.115.1.150","article-title":"Immune responses to a soluble schistosomal egg antigen preparation during chronic primary infection with Schistosoma mansoni","volume":"115","author":"Colley","year":"1975","journal-title":"J. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/j.1365-2567.2004.02083.x","article-title":"Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice","volume":"114","author":"Singh","year":"2005","journal-title":"Immunology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11882-009-0085-3","article-title":"Chronic Helminth Infections Protect Against Allergic Diseases by Active Regulatory Processes","volume":"10","author":"Hermelijn","year":"2010","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.4049\/jimmunol.177.3.1628","article-title":"Intestinal Helminths Protect in a Murine Model of Asthma","volume":"177","author":"Kitagaki","year":"2006","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1385\/CRIAI:26:1:15","article-title":"Parasites and the Hygiene Hypothesis","volume":"26","author":"Yazdanbakhsh","year":"2004","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"S466","DOI":"10.1016\/S0091-6749(00)90044-7","article-title":"Prevalence and etiology of asthma","volume":"105","author":"Beasley","year":"2000","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_54","first-page":"1297","article-title":"Primary Allergic Sensitization to Environmental Antigens: Perinatal T Cell Priming as a Determinant of Responder Phenotype in Adulthood","volume":"183","author":"Holt","year":"1996","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_55","first-page":"263","article-title":"The Th1\/Th2 paradigm","volume":"18","author":"Romagnani","year":"1997","journal-title":"Curr. Opin. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1126\/science.296.5567.490","article-title":"Allergy, parasites, and the hygiene hypothesis","volume":"296","author":"Yazdanbakhs","year":"2002","journal-title":"Science"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000024433","article-title":"Inverse association between skin response to aeroallergens and Schistosoma mansoni infection","volume":"123","author":"Araujo","year":"2000","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/S0140-6736(00)03206-2","article-title":"Decreased atopy in children infected with Schistosoma haematobium: A role for parasite-induced interleukin-10","volume":"356","author":"Rodrigues","year":"2000","journal-title":"Lancet"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1046\/j.1365-2222.2001.00987.x","article-title":"Atopy, intestinal helminth infection and total serum IgE in rural and urban adult Gambian communities","volume":"31","author":"Nyan","year":"2001","journal-title":"Clin. Exp. Allergy"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1093\/oxfordjournals.epirev.a036285","article-title":"Parasites and asthma: Predictive or protective?","volume":"7","author":"Masters","year":"1985","journal-title":"Epidemiol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1096\/fj.99-0885hyp","article-title":"Does the failure to acquire helminthic parasites predispose to Crohn\u2019s disease?","volume":"14","author":"Elliott","year":"2000","journal-title":"FASEB J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1191\/1352458504ms1087oa","article-title":"A prospective study of conditions associated with multiple sclerosis in a cohort of 658 consecutive outpatients attending a multiple sclerosis clinic","volume":"10","author":"Edwards","year":"2004","journal-title":"Mult. Scler."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/S0140-6736(00)04067-8","article-title":"Relation between occurrence of type 1 diabetes and asthma","volume":"357","author":"Stene","year":"2001","journal-title":"Lancet"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1056\/NEJMra020100","article-title":"The effect of infections on susceptibility to autoimmune and allergic diseases","volume":"347","author":"Bach","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/35095579","article-title":"The germless allergic disease: Revisiting the hygiene hypothesis","volume":"1","author":"Santeliz","year":"2001","journal-title":"Nat. Rev. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S0140-6736(01)06579-5","article-title":"Independent effects of intestinal parasite infection and domestic allergen exposure on risk of wheeze in Ethiopia: A nested case-control study","volume":"358","author":"Scrivener","year":"2001","journal-title":"Lancet"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nature11550","article-title":"Diversity, stability and resilience of the human gut microbiota","volume":"489","author":"Lozupone","year":"2012","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4578","DOI":"10.1073\/pnas.1000081107","article-title":"Succession of microbial consortia in the developing infant gut microbiome","volume":"108","author":"Koenig","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/nature11053","article-title":"Human gut microbiome viewed across age and geography","volume":"486","author":"Yatsunenko","year":"2012","journal-title":"Nature"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/j.jaci.2011.02.012","article-title":"Influence of gastrointestinal commensal bacteria on the immune responses that mediate allergy and asthma","volume":"127","author":"McLoughlin","year":"2011","journal-title":"J Allergy Clin. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"O\u2019Mahony, C., Scully, P., O\u2019Mahony, D., Murphy, S., O\u2019Brien, F., Lyons, A., Sherlock, G., John MacSharry, J., Kiely, B., and Shanahan, F. (2008). Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000112"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1365-2222.2009.03344.x","article-title":"Lactic acid bacteria differ in their ability to induce functional regulatory T cells in humans","volume":"40","author":"Timmerman","year":"2010","journal-title":"Clin. Exp. Allergy J. Br. Soc. Allergy Clin. Immunol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1126\/science.1198469","article-title":"Induction of colonic regulatory T cells by indigenous Clostridium species","volume":"331","author":"Atarashi","year":"2011","journal-title":"Science"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature12721","article-title":"Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells","volume":"504","author":"Furusawa","year":"2013","journal-title":"Nature"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1126\/science.1241165","article-title":"The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis","volume":"341","author":"Smith","year":"2013","journal-title":"Science"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1038\/nature08530","article-title":"Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43","volume":"461","author":"Maslowski","year":"2009","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1067\/mai.2001.111237","article-title":"Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing","volume":"107","author":"Kalliomaki","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1542\/peds.2005-2824","article-title":"Factors influencing the composition of the intestinal microbiota in early infancy","volume":"118","author":"Penders","year":"2006","journal-title":"Pediatrics"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5149","DOI":"10.1016\/j.vaccine.2014.07.052","article-title":"A role for impaired regulatory T cell function in adverse responses to aluminum adjuvant-containing vaccines in genetically susceptible individuals","volume":"32","author":"Terhune","year":"2014","journal-title":"Vaccine"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1542\/peds.111.3.653","article-title":"Addressing parents\u2019 concerns: Do vaccines cause allergic or autoimmune diseases?","volume":"111","author":"Offit","year":"2003","journal-title":"Pediatrics"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1365-2567.2004.01869.x","article-title":"Noramal human pregnancy is associated with an elevation in the immune suppressive CD25+ CD4+ regulatory T-cell subset","volume":"112","author":"Somerset","year":"2004","journal-title":"Immunology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/ncpneuro0832","article-title":"The role of regulatory T cells in multiple sclerosis","volume":"4","author":"Zozulya","year":"2008","journal-title":"Nat. Clin. Pract. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1067\/mai.2003.1570","article-title":"Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy","volume":"111","author":"Francis","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e166","DOI":"10.1111\/j.1399-3038.2009.00870.x","article-title":"Induction of IL-10+CD4+CD25+ regulatory T cells with decreased NF-kB expression during immunotherapy","volume":"21","author":"Tsai","year":"2010","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_85","first-page":"70","article-title":"Mathematical modeling of allergy and specific immunotherapy: Th1 Th2\u2013Treg interactions","volume":"269","author":"Metzner","year":"2010","journal-title":"J. Theor. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1111\/j.1398-9995.2011.02589.x","article-title":"Immunological mechanisms of allergen-specific immunotherapy","volume":"66","author":"Jutel","year":"2011","journal-title":"Allergy"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1002\/eji.1830260713","article-title":"Neonatal and early life immune responses to various forms of vaccine antigens qualitatively differ from adult responses: Predominance of a TH2-biased pattern which persists after adult boosting","volume":"26","author":"Barrios","year":"1996","journal-title":"Eur. J. Immunol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.4049\/jimmunol.160.10.4730","article-title":"Transplacental priming of the human immune system to environmental allergens: Universal skewing of initial T cell responses toward the TH2 cytokine profile","volume":"160","author":"Prescott","year":"1998","journal-title":"J. Immunol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1046\/j.1365-2222.1998.028s5039.x","article-title":"Reciprocal age-related patterns of allergen-specific T-cell immunity in normal vs. atopic infants","volume":"28","author":"Prescott","year":"1998","journal-title":"Clin. Exp. Allergy"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1086\/315458","article-title":"Influence of human immunodeficiency virus-infected maternal environment on development of infant interleukin-12 production","volume":"181","author":"Chougnet","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"AB10","DOI":"10.1016\/j.jaci.2014.12.966","article-title":"The Differential Relationship between Regulatory T-Cells and Age in Children with Food Allergy","volume":"135","author":"Prince","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1002\/1521-4141(200206)32:6<1621::AID-IMMU1621>3.0.CO;2-Q","article-title":"Antigen specific T cell suppression by human CD4+CD25+ regulatory T cells","volume":"32","author":"Taams","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/S0140-6736(04)15592-X","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":"363","author":"Ling","year":"2004","journal-title":"Lancet"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1067\/mai.2003.1412","article-title":"Human CD4+CD25+ T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production","volume":"111","author":"Bellinghausen","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1084\/jem.20052211","article-title":"Regulatory T cells and IL-10 in allergic inflammation","volume":"202","author":"Hawrylowicz","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1084\/jem.20032058","article-title":"Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells","volume":"199","author":"Akdis","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/S0091-6749(96)70197-5","article-title":"Interleukin-10 regulation in normal subjects and patients with asthma","volume":"97","author":"Borish","year":"1996","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/S0140-6736(98)85018-6","article-title":"Haplotype associated with low interleukin-10 production in patients with severe asthma","volume":"352","author":"Lim","year":"1998","journal-title":"Lancet"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/S0140-6736(05)17704-6","article-title":"An immunoepidemiological approach to asthma: Identification of in-vitro T-cell response patterns associated with different wheezing phenotypes in children","volume":"365","author":"Heaton","year":"2005","journal-title":"Lancet"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1046\/j.1600-065X.2003.00079.x","article-title":"Dendritic cells: Regulators of alloimmunity and opportunities for tolerance induction","volume":"196","author":"Morelli","year":"2003","journal-title":"Immunol. Rev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S1074-7613(03)00113-4","article-title":"Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo","volume":"18","author":"Wakkach","year":"2003","journal-title":"Immunity"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1159\/000094255","article-title":"Interleukin-10-Treated Dendritic Cells Do Not Inhibit Th2 Immune Responses in Ovalbumin\/Alum-Sensitized Mice","volume":"141","author":"Bellinghausen","year":"2005","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3109\/1547691X.2012.708366","article-title":"How aluminum adjuvants could promote and enhance non-target IgE synthesis in a genetically-vulnerable sub-population","volume":"10","author":"Terhune","year":"2012","journal-title":"J. Immunotoxicol."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Kool, M., Hammad, H., and Lambrecht, B.N. (2012). Cellular networks controlling Th2 polarization in allergy and immunity. F1000 Biol. Rep., 4.","DOI":"10.3410\/B4-6"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1128\/IAI.69.2.1151-1159.2001","article-title":"The Common Vaccine Adjuvant Aluminum Hydroxide Up-Regulates Accessory Properties of Human Monocytes via an Interleukin-4-Dependent Mechanism","volume":"69","author":"Ulanova","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"18169","DOI":"10.1073\/pnas.0703642104","article-title":"Antagonistic nature of T helper 1\/2 development programs in opposing peripheral induction of Foxp3+ regulatory T cells","volume":"104","author":"Wei","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"21597","DOI":"10.1074\/jbc.272.34.21597","article-title":"Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specificexpression of the interleukin-5 gene","volume":"272","author":"Zhang","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0092-8674(00)80240-8","article-title":"The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells","volume":"89","author":"Zheng","year":"1997","journal-title":"Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"14955","DOI":"10.1074\/jbc.M801123200","article-title":"STAT6 inhibits TGF-beta1 mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor","volume":"283","author":"Takaki","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Mantel, P.Y., Kuipers, H., Boyman, O., Rhyner, C., Ouaked, N., R\u00fcckert, B., Karagiannidis, C., Lambrecht, B.N., Hendriks, R.W., and Crameri, R. (2007). GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol., 5.","DOI":"10.1371\/journal.pbio.0050329"},{"key":"ref_111","first-page":"406","article-title":"Mechanism of immunopotentiation and safety of aluminum adjunvants","volume":"3","author":"HogenEsch","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1080\/21645515.2014.1004026","article-title":"Advances in aluminum hydroxide-based adjuvant research and its mechanism","volume":"11","author":"He","year":"2015","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1086\/320996","article-title":"Heterogeneity in diphtheria-tetanus-acellular pertussis vaccine-specific cellular immunity during infancy: Relationship to variations in the kinetics of postnatal maturation of systemic Th1 function","volume":"184","author":"Rowe","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_114","unstructured":"Hoyt, A., Heymann, P., Schuyler, A., Commins, S., and Platts-Mills, T. (2015, January 5\u20136). Changes in IgE Levels Following One-Year Immunizations in Two Children with Food Allergy. Proceedings of the WAO Symposium on Food Allergy & the Microbiome, Miami, FL, USA."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1016\/S0264-410X(99)00480-6","article-title":"IgE sensitization to gelatin: The probable role of gelatin-containing diphtheria-tetanus-acellular pertussis (DTaP) vaccines","volume":"18","author":"Sakaquchi","year":"2000","journal-title":"Vaccine"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.coi.2009.01.004","article-title":"Mechanism of action of clinically approved adjuvants","volume":"21","author":"Lambercht","year":"2009","journal-title":"Curr. Opin. Immunol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0300-483X(03)00043-X","article-title":"Species differences in the structure and function of the immune system","volume":"188","author":"Haley","year":"2003","journal-title":"Toxicology"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1016\/j.vaccine.2013.05.107","article-title":"Kinetics of the inflammatory response following intramuscular injection of aluminum adjuvant","volume":"31","author":"Lu","year":"2013","journal-title":"Vaccine"},{"key":"ref_119","unstructured":"Paul, W.E. (2003). Immunoglobulin class switching. Fundamental Immunology, Lippincott-Raven."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"353","DOI":"10.4049\/jimmunol.150.2.353","article-title":"Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production","volume":"150","author":"Almerigogna","year":"1993","journal-title":"J. Immunol."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/15\/5\/901\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:03:00Z","timestamp":1760194980000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/15\/5\/901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,5,3]]},"references-count":120,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["ijerph15050901"],"URL":"https:\/\/doi.org\/10.3390\/ijerph15050901","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,5,3]]}}}