Biomarkers for monitoring clinical efficacy of allergen immunotherapy for allergic rhinoconjunctivitis and allergic asthma: an EAACI Position Paper

Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.

[1]  S. Durham,et al.  T lymphocytes expressing CCR3 are increased in allergic rhinitis compared with non‐allergic controls and following allergen immunotherapy , 2007, Allergy.

[2]  A. Sheikh,et al.  Sublingual immunotherapy for allergic conjunctivitis: Cochrane systematic review and meta‐analysis , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[3]  H. Ipsen,et al.  A double‐blind placebo‐controlled birch allergy vaccination study II: correlation between inhibition of IgE binding, histamine release and facilitated allergen presentation , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[4]  S. Durham,et al.  Basophil expression of diamine oxidase: a novel biomarker of allergen immunotherapy response. , 2015, The Journal of allergy and clinical immunology.

[5]  E. Terho,et al.  Increased expression of allergen‐induced in vitro interleukin‐10 and interleukin‐18 mRNA in peripheral blood mononuclear cells of allergic rhinitis patients after specific immunotherapy , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[6]  B. Rogala,et al.  Effect of allergen-specific immunotherapy on platelet secretory activity in patients with grass-pollen allergy. , 2006, Vaccine.

[7]  Helen E. Smith,et al.  Randomized controlled trial of high-dose sublingual immunotherapy to treat seasonal allergic rhinitis. , 2004, The Journal of allergy and clinical immunology.

[8]  K. Reich,et al.  Immunologic effects and tolerability profile of in-season initiation of a standardized-quality grass allergy immunotherapy tablet: a phase III, multicenter, randomized, double-blind, placebo-controlled trial in adults with grass pollen-induced rhinoconjunctivitis. , 2011, Clinical therapeutics.

[9]  S. Durham,et al.  Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. , 2011, The Journal of allergy and clinical immunology.

[10]  P. Potter,et al.  Clinical and cytokine responses to house dust mite sublingual immunotherapy. , 2015, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[11]  M. Jutel,et al.  Allergen-specific immunotherapy with recombinant grass pollen allergens. , 2005, The Journal of allergy and clinical immunology.

[12]  R. O’Hehir,et al.  Functional regulatory T cells and allergen immunotherapy , 2010, Current opinion in allergy and clinical immunology.

[13]  P. Korošec,et al.  The clinical utility of basophil activation testing in diagnosis and monitoring of allergic disease , 2015, Allergy.

[14]  Y. Okamoto,et al.  A Randomized Controlled Trial of Sublingual Immunotherapy for Japanese Cedar Pollinosis , 2007, International Archives of Allergy and Immunology.

[15]  Allergen injection immunotherapy for seasonal allergic rhinitis. , 2007, The Cochrane database of systematic reviews.

[16]  S. Durham,et al.  Mechanisms of immunotherapy to aeroallergens , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[17]  S. Durham,et al.  Grass pollen immunotherapy induces Foxp3-expressing CD4+ CD25+ cells in the nasal mucosa. , 2008, The Journal of allergy and clinical immunology.

[18]  A. Togias,et al.  Effect of grass pollen immunotherapy on clinical and local immune response to nasal allergen challenge , 2015, Allergy.

[19]  S. Rak,et al.  Effect of 2-year placebo-controlled immunotherapy on airway symptoms and medication in patients with birch pollen allergy. , 2002, The Journal of allergy and clinical immunology.

[20]  R. Naclerio,et al.  Immunotherapy decreases antigen-induced eosinophil cell migration into the nasal cavity. , 1991, The Journal of allergy and clinical immunology.

[21]  L. Klimek,et al.  High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: a double-blind, placebo-controlled study. , 2012, The Journal of allergy and clinical immunology.

[22]  E. Knol,et al.  The role of basophils in the pathogenesis of allergic disease , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[23]  T. Haahtela,et al.  Pollen-specific rush immunotherapy: clinical efficacy and effects on antibody concentrations. , 2001, Annals of Allergy, Asthma & Immunology.

[24]  S. Saitoh,et al.  Effect of Japanese cedar specific immunotherapy on allergen-specific T(H)2 cells in peripheral blood. , 2013, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[25]  A. Ikinciogullari,et al.  Short-Term Preseasonal Immunotherapy: Is Early Clinical Efficacy Related to the Basophil Response? , 2014, International Archives of Allergy and Immunology.

[26]  S. Spector,et al.  Allergen immunotherapy: a practice parameter third update. , 2007, The Journal of allergy and clinical immunology.

[27]  Mingqiang He,et al.  Cytokine Responses to Specific Immunotherapy in House Dust Mite-Induced Allergic Rhinitis Patients , 2015, Inflammation.

[28]  C. Bachert,et al.  Diagnostic tools in Rhinology EAACI position paper , 2011, Clinical and translational allergy.

[29]  A. Kober,et al.  Quantitation of Mouse-Human Chimeric Allergen Specific IgE Antibodies with ImmunoCAP™ Technology , 2006 .

[30]  S. Durham,et al.  Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3‐expressing cells and elevated allergen‐specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E‐facilitated allergen binding to B cells , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[31]  O. Kalayci,et al.  The effects of grass pollen allergoid immunotherapy on clinical and immunological parameters in children with allergic rhinitis , 2006, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[32]  T. Kündig,et al.  Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy. , 2009, The Journal of allergy and clinical immunology.

[33]  S. Durham,et al.  Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1 : Th2 cytokine ratios , 2002, Immunology.

[34]  J Bousquet,et al.  Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. , 1998, The Journal of allergy and clinical immunology.

[35]  M. Willheim,et al.  Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T‐cell clones specific for Phi p 1, a major grass pollen allergen , 1997, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[36]  L. Klimek,et al.  Specific subcutaneous immunotherapy with recombinant grass pollen allergens: first randomized dose‐ranging safety study , 2012, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[37]  D. Caillaud,et al.  Sublingual‐swallow immunotherapy (SLIT) in patients with asthma due to house‐dust mites: a double‐blind, placebo‐controlled study , 1999, Allergy.

[38]  R. Dahl,et al.  Pretreatment IgE sensitization patterns determine the molecular profile of the IgG4 response during updosing of subcutaneous immunotherapy with timothy grass pollen extract. , 2016, The Journal of allergy and clinical immunology.

[39]  Stephen J Galli,et al.  Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). , 2014, The Journal of allergy and clinical immunology.

[40]  R. O’Hehir,et al.  House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells. , 2009, American journal of respiratory and critical care medicine.

[41]  S. Durham,et al.  The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses. , 2006, Journal of immunological methods.

[42]  M. Pallardy,et al.  Changes in markers associated with dendritic cells driving the differentiation of either TH2 cells or regulatory T cells correlate with clinical benefit during allergen immunotherapy. , 2016, The Journal of allergy and clinical immunology.

[43]  R. Van Ree,et al.  International consensus on allergy immunotherapy. , 2015, The Journal of allergy and clinical immunology.

[44]  H. Malling,et al.  Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy? , 2013, The Journal of allergy and clinical immunology.

[45]  F. Horak,et al.  Changes in basophil activation during grass‐pollen sublingual immunotherapy do not correlate with clinical efficacy , 2011, Allergy.

[46]  P. Scheinmann,et al.  Assessment of sublingual immunotherapy efficacy in children with house dust mite‐induced allergic asthma optimally controlled by pharmacologic treatment and mite‐avoidance measures , 2007, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[47]  M. Yılmaz,et al.  Two year follow-up of clinical and inflammation parameters in children monosensitized to mites undergoing subcutaneous and sublingual immunotherapy. , 2013, Asian Pacific journal of allergy and immunology.

[48]  E. Valovirta,et al.  Clinical outcome and IL‐17, IL‐23, IL‐27 and FOXP3 expression in peripheral blood mononuclear cells of pollen‐allergic children during sublingual immunotherapy , 2010, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[49]  S. Durham,et al.  Cell-free detection of allergen-IgE cross-linking with immobilized phase CD23: inhibition by blocking antibody responses after immunotherapy. , 2013, The Journal of allergy and clinical immunology.

[50]  O. Pfaar,et al.  Depigmented–polymerized mixed grass/birch pollen extract immunotherapy is effective in polysensitized patients , 2013, Allergy.

[51]  D. Umetsu,et al.  Clinical efficacy of microencapsulated timothy grass pollen extract in grass-allergic individuals. , 2004, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[52]  S. Durham,et al.  Allergen immunotherapy: does it work and, if so, how and for how long? , 2000, Thorax.

[53]  T. Arinami,et al.  Apolipoprotein A-IV is a candidate target molecule for the treatment of seasonal allergic rhinitis. , 2010, The Journal of allergy and clinical immunology.

[54]  B. Samoliński,et al.  A follow‐up study of immunotherapy‐treated birch‐allergic patients: effect on the expression of chemokines in the nasal mucosa , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[55]  M. Calderón,et al.  Tolerability during double-blind randomized phase I trials with the house dust mite allergy immunotherapy tablet in adults and children. , 2014, Journal of investigational allergology & clinical immunology.

[56]  D. Ebo,et al.  Analyzing histamine release by flow cytometry (HistaFlow): a novel instrument to study the degranulation patterns of basophils. , 2012, Journal of immunological methods.

[57]  S. Durham,et al.  Optimisation of grass pollen nasal allergen challenge for assessment of clinical and immunological outcomes. , 2012, Journal of immunological methods.

[58]  L. Lichtenstein,et al.  IgA and IgG anti-ragweed antibodies in nasal secretions. Quantitative measurements of antibodies and correlation with inhibition of histamine release. , 1976, The Journal of clinical investigation.

[59]  I. Barlan,et al.  A novel approach in allergen-specific immunotherapy: combination of sublingual and subcutaneous routes. , 2011, The Journal of allergy and clinical immunology.

[60]  J. Bousquet,et al.  Recommendations for the standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. , 2014, Allergy.

[61]  U. Krishnan,et al.  EpCAM is a putative stem marker in retinoblastoma and an effective target for T-cell-mediated immunotherapy , 2012, Molecular vision.

[62]  P. Korošec,et al.  Sustained effect of grass pollen subcutaneous immunotherapy on suppression of allergen‐specific basophil response; a real‐life, nonrandomized controlled study , 2015, Allergy.

[63]  B. Niggemann,et al.  Lack of Detectable Alterations in Immune Responses during Sublingual Immunotherapy in Children with Seasonal Allergic Rhinoconjunctivitis to Grass Pollen , 2005, International Archives of Allergy and Immunology.

[64]  D. Bernstein,et al.  Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults. , 2011, The Journal of allergy and clinical immunology.

[65]  P. Devillier,et al.  Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber. , 2009, The Journal of allergy and clinical immunology.

[66]  C. Akdis,et al.  Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens. , 2014, The Journal of allergy and clinical immunology.

[67]  J. Schroeder,et al.  The role of the basophil in allergic inflammation , 1995, Allergy.

[68]  O. Gulbahar,et al.  Desensitization Effect of Preseasonal Seven-Injection Allergoid Immunotherapy with Olive Pollen on Basophil Activation: The Efficacy of Olive Pollen-Specific Preseasonal Allergoid Immunotherapy on Basophils , 2012, International Archives of Allergy and Immunology.

[69]  E. Valovirta,et al.  Sublingual immunotherapy in children modulates allergen‐induced in vitro expression of cytokine mRNA in PBMC , 2006, Allergy.

[70]  N. Martinelli,et al.  Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy. , 2009, The Journal of allergy and clinical immunology.

[71]  S. Fujieda,et al.  Long-term sublingual immunotherapy for Japanese cedar pollinosis and the levels of IL-17A and complement components 3a and 5a. , 2015, Cytokine.

[72]  A. Togias,et al.  Effect of 2 Years of Treatment With Sublingual Grass Pollen Immunotherapy on Nasal Response to Allergen Challenge at 3 Years Among Patients With Moderate to Severe Seasonal Allergic Rhinitis: The GRASS Randomized Clinical Trial , 2017, JAMA.

[73]  S. Durham,et al.  Inhibition of allergen-IgE binding to B cells by IgG antibodies after grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[74]  S. Galli,et al.  Toward precision medicine and health: Opportunities and challenges in allergic diseases. , 2016, The Journal of allergy and clinical immunology.

[75]  C. Akdis,et al.  Advances in allergen immunotherapy: Aiming for complete tolerance to allergens , 2015, Science Translational Medicine.

[76]  Chengshuo Wang,et al.  Enhancement of the Frequency and Function of IL-10-Secreting Type I T Regulatory Cells after 1 Year of Cluster Allergen-Specific Immunotherapy , 2012, International Archives of Allergy and Immunology.

[77]  S. Vieths,et al.  Environmental exposure chambers in allergen immunotherapy trials: Current status and clinical validation needs. , 2015, The Journal of allergy and clinical immunology.

[78]  R. Jacobs,et al.  Responses to ragweed pollen in a pollen challenge chamber versus seasonal exposure identify allergic rhinoconjunctivitis endotypes. , 2012, The Journal of allergy and clinical immunology.

[79]  A. Linneberg,et al.  Performance evaluation of a specific IgE assay developed for the ADVIA centaur immunoassay system. , 2004, Clinical biochemistry.

[80]  P. Chakraborty,et al.  Phoenix sylvestris Roxb pollen allergy: a 2-year randomized controlled trial and follow-up study of immunotherapy in patients with seasonal allergy in an agricultural area of West Bengal, India. , 2006, Journal of investigational allergology & clinical immunology.

[81]  L. Cardell,et al.  CD‐sens: a biological measure of immunological changes stimulated by ASIT , 2009, Allergy.

[82]  S. Durham,et al.  Allergen immunotherapy and tolerance. , 2013, Allergology international : official journal of the Japanese Society of Allergology.

[83]  M. Blaiss,et al.  Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents. , 2011, The Journal of allergy and clinical immunology.

[84]  L. Morabito,et al.  Clinical and immunologic effects of long‐term sublingual immunotherapy in asthmatic children sensitized to mites:a double‐blind, placebo‐controlled study , 2000, Allergy.

[85]  A. Yalcin,et al.  Soluble trail as a marker of efficacy of allergen-specific immunotherapy in patients with allergic rhinoconjunctivitis , 2012, Medical science monitor : international medical journal of experimental and clinical research.

[86]  Y. Nakai,et al.  The effect of immunotherapy on the serum levels of eosinophil cationic protein in seasonal allergic rhinitis. , 1997, Clinical otolaryngology and allied sciences.

[87]  William H. Yang,et al.  Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. , 2006, The Journal of allergy and clinical immunology.

[88]  S. Durham,et al.  Rhinitis , sinusitis , and upper airway disease SQ-standardized sublingual grass immunotherapy : Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial , 2012 .

[89]  B. Rogala,et al.  Effect of allergen-specific immunotherapy on plasma level of platelet factor 4 (PF-4) and beta-thromboglobulin (beta-TG), platelet activation markers in patients with house dust mite allergy. , 2007, Vaccine.

[90]  J. Savolainen,et al.  Three-Year Follow-Up Study of Allergen-Induced in vitro Cytokine and Signalling Lymphocytic Activation Molecule mRNA Responses in Peripheral Blood Mononuclear Cells of Allergic Rhinitis Patients Undergoing Specific Immunotherapy , 2009, International Archives of Allergy and Immunology.

[91]  H. Wang,et al.  A double‐blind, placebo‐controlled study of house dust mite immunotherapy in Chinese asthmatic patients , 2006, Allergy.

[92]  M. Larché,et al.  Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. , 2013, The Journal of allergy and clinical immunology.

[93]  S. Durham,et al.  Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. , 2010, The Journal of allergy and clinical immunology.

[94]  S. Durham,et al.  Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. , 2008, The Journal of allergy and clinical immunology.

[95]  N. Arora,et al.  Clinico‐immunological changes post‐immunotherapy with Periplaneta americana , 2011, European journal of clinical investigation.

[96]  C. Akdis,et al.  Impact of Sublingual Immunotherapy on Specific Antibody Levels in Asthmatic Children Allergic to House Dust Mites , 2005, International Archives of Allergy and Immunology.

[97]  R. Coffman,et al.  Allergen‐specific T cell responses to immunotherapy monitored by CD154 and intracellular cytokine expression , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[98]  B. Wüthrich,et al.  Intralymphatic allergen administration renders specific immunotherapy faster and safer: A randomized controlled trial , 2008, Proceedings of the National Academy of Sciences.

[99]  A. Eifan,et al.  Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: an open randomized controlled trial , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[100]  G. Ciprandi,et al.  Serum IL-9 levels and sublingual immunotherapy: preliminary report. , 2011, Journal of biological regulators and homeostatic agents.

[101]  G. Marseglia,et al.  Adipokines and sublingual immunotherapy: preliminary report. , 2009, Human immunology.

[102]  T. Casale,et al.  Update on allergy immunotherapy: American Academy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical Immunology/PRACTALL consensus report. , 2013, The Journal of allergy and clinical immunology.

[103]  R. Zeldin,et al.  Heterogeneity of antibody responses among clinical responders during grass pollen sublingual immunotherapy , 2013, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[104]  A. Togias,et al.  Local and systemic effects of cat allergen nasal provocation , 2015, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[105]  G. Canonica,et al.  Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis , 1998, The Lancet.

[106]  G. Viegi,et al.  Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 * , 2008, Allergy.

[107]  R. Cooke,et al.  SEROLOGICAL EVIDENCE OF IMMUNITY WITH COEXISTING SENSITIZATION IN A TYPE OF HUMAN ALLERGY (HAY FEVER) , 1935, The Journal of experimental medicine.

[108]  P. Demoly,et al.  In vivo diagnosis of allergic diseases—allergen provocation tests , 2015, Allergy.

[109]  G. Canonica,et al.  Sublingual immunotherapy for Alternaria-induced allergic rhinitis: a randomized placebo-controlled trial. , 2010, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[110]  J. Bousquet,et al.  Advances in allergen-microarray technology for diagnosis and monitoring of allergy: the MeDALL allergen-chip. , 2014, Methods.

[111]  A. Louise,et al.  A regulatory dendritic cell signature correlates with the clinical efficacy of allergen-specific sublingual immunotherapy. , 2012, The Journal of allergy and clinical immunology.

[112]  C. Fanta,et al.  Systemic Immunological Changes Induced by Administration of Grass Pollen Allergens via the Oral Mucosa during Sublingual Immunotherapy , 1999, International Archives of Allergy and Immunology.

[113]  M. Sormani,et al.  Relationship between soluble HLA-G and HLA-A,-B,-C serum levels, and interferon-gamma production after sublingual immunotherapy in patients with allergic rhinitis. , 2008, Human immunology.

[114]  S. Durham,et al.  Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-gamma. , 1996, The Journal of allergy and clinical immunology.

[115]  International Conference on Harmonisation; Guidance on E15 Pharmacogenomics Definitions and Sample Coding; Availability. Notice. , 2008, Federal register.

[116]  H. Nelson,et al.  Response to sublingual immunotherapy with grass pollen extract: monotherapy versus combination in a multiallergen extract. , 2009, The Journal of allergy and clinical immunology.

[117]  C. Rhee,et al.  Sublingual immunotherapy in allergic rhinitis , 2011, Asia Pacific allergy.

[118]  R. Valenta,et al.  Monitoring Allergen Immunotherapy Effects by Microarray , 2016, Current Treatment Options in Allergy.

[119]  A. Salapatek,et al.  Double‐blind, placebo‐controlled, dose‐ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber , 2013, Allergy.

[120]  R. Van Ree,et al.  A randomized DBPC trial to determine the optimal effective and safe dose of a SLIT‐birch pollen extract for the treatment of allergic rhinitis: results of a phase II study , 2015, Allergy.

[121]  F. Horak,et al.  Allergen‐specific CD4+ T cell responses in peripheral blood do not predict the early onset of clinical efficacy during grass pollen sublingual immunotherapy , 2012, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[122]  A. Sheikh,et al.  Sublingual immunotherapy for treating allergic conjunctivitis. , 2011, The Cochrane database of systematic reviews.

[123]  A. Nordheim,et al.  Identification of CD13, CD107a, and CD164 as novel basophil-activation markers and dissection of two response patterns in time kinetics of IgE-dependent upregulation , 2005, Cell Research.

[124]  S. Voltolini,et al.  Sublingual immunotherapy in Parietaria pollen-induced rhinitis: a double-blind study. , 1995, Journal of investigational allergology & clinical immunology.

[125]  M. Strand,et al.  Immunologic response to administration of standardized dog allergen extract at differing doses. , 2006, The Journal of allergy and clinical immunology.

[126]  R. Mösges,et al.  Sublingual immunotherapy in pollen-induced seasonal rhinitis and conjunctivitis: a randomized controlled trial. , 2007, Acta dermatovenerologica Alpina, Pannonica, et Adriatica.

[127]  C. Akdis,et al.  IL-10-overexpressing B cells regulate innate and adaptive immune responses. , 2015, The Journal of allergy and clinical immunology.

[128]  R. Aalberse,et al.  IgG4 breaking the rules , 2002, Immunology.

[129]  J. Oliver,et al.  Negative regulation of FcepsilonRI signaling by FcgammaRII costimulation in human blood basophils. , 2000, The Journal of allergy and clinical immunology.

[130]  V. Backer,et al.  Immunological comparison of allergen immunotherapy tablet treatment and subcutaneous immunotherapy against grass allergy , 2014, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[131]  R. Naclerio,et al.  Responses to ragweed-pollen nasal challenge before and after immunotherapy. , 1989, The Journal of allergy and clinical immunology.

[132]  S. Durham,et al.  Functional rather than immunoreactive levels of IgG4 correlate closely with clinical response to grass pollen immunotherapy , 2012, Allergy.

[133]  L. Cosmi,et al.  Sublingual immunotherapy with Dermatophagoides monomeric allergoid down‐regulates allergen‐specific immunoglobulin E and increases both interferon‐γ‐ and interleukin‐10‐production , 2006, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[134]  B. Stadler,et al.  A long-term follow-up study of hyposensitization with immunoblotting. , 1990, The Journal of allergy and clinical immunology.

[135]  F. Horak,et al.  Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives , 2008, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[136]  I. Barlan,et al.  Efficacy of long‐term sublingual immunotherapy as an adjunct to pharmacotherapy in house dust mite‐allergic children with asthma , 2007, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[137]  Lei Cheng,et al.  Fast onset of action of sublingual immunotherapy in house dust mite‐induced allergic rhinitis: A multicenter, randomized, double‐blind, placebo‐controlled trial , 2013, The Laryngoscope.

[138]  D. DeMets,et al.  Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework , 2001, Clinical pharmacology and therapeutics.

[139]  S. Durham,et al.  Grass Pollen Immunotherapy Induces Mucosal and Peripheral IL-10 Responses and Blocking IgG Activity1 , 2004, The Journal of Immunology.

[140]  W. Busse,et al.  Food , drug , insect sting allergy , and anaphylaxis House dust mite sublingual immunotherapy : Results of a US trial , 2011 .

[141]  P. Kardos,et al.  Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial. , 2010, The Journal of allergy and clinical immunology.

[142]  P. Korošec,et al.  Immunoglobulin G‐dependent changes in basophil allergen threshold sensitivity during birch pollen immunotherapy , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[143]  S. Komune,et al.  Phase I/II study of oral immunotherapy with Cry j1-galactomannan conjugate for Japanese cedar pollinosis. , 2014, Auris, nasus, larynx.

[144]  L. Klimek,et al.  Efficacy of grass pollen sublingual immunotherapy for three consecutive seasons and after cessation of treatment: the ECRIT study , 2009, Allergy.

[145]  J. Oliver,et al.  Negative regulation of FcϵRI signaling by FcγRII costimulation in human blood basophils , 2000 .

[146]  S. Durham,et al.  Systematic reviews of sublingual immunotherapy (SLIT) , 2011, Allergy.

[147]  J. Lidholm,et al.  Kinetics, cross‐reactivity, and specificity of Bet v 1‐specific IgG4 antibodies induced by immunotherapy with birch pollen , 2013, Allergy.

[148]  G. Marseglia,et al.  Sublingual immunotherapy induces spirometric improvement associated with IL-10 production: preliminary reports. , 2006, International immunopharmacology.

[149]  C. Rondón,et al.  Initial immunological changes as predictors for house dust mite immunotherapy response , 2015, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[150]  R. Dahl,et al.  Early improvement in basophil sensitivity predicts symptom relief with grass pollen immunotherapy. , 2014, The Journal of allergy and clinical immunology.

[151]  G. Canonica,et al.  Double-blind placebo-controlled evaluation of sublingual-swallow immunotherapy with standardized Parietaria judaica extract in children with allergic rhinoconjunctivitis. , 1999, The Journal of allergy and clinical immunology.

[152]  M. Yılmaz,et al.  Effect of One-Year Subcutaneous and Sublingual Immunotherapy on Clinical and Laboratory Parameters in Children with Rhinitis and Asthma: A Randomized, Placebo-Controlled, Double-Blind, Double-Dummy Study , 2011, International Archives of Allergy and Immunology.

[153]  G. Canonica,et al.  An update on allergen immunotherapy and asthma , 2014, Current opinion in pulmonary medicine.

[154]  P. Valent,et al.  The Basophil-Specific Ectoenzyme E-NPP3 (CD203c) as a Marker for Cell Activation and Allergy Diagnosis , 2004, International Archives of Allergy and Immunology.

[155]  L. Lichtenstein,et al.  Antibody response following immunotherapy in ragweed hay fever: Allpyral vs. whole ragweed extract. , 1968, The Journal of allergy.

[156]  S. Durham,et al.  Grass pollen sublingual immunotherapy for seasonal rhinoconjunctivitis: a randomized controlled trial , 2002, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[157]  M. Chou,et al.  Clinical and immunologic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double‐blind, randomized, placebo‐controlled study , 2006, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[158]  Franz König,et al.  Allergen-specific nasal IgG antibodies induced by vaccination with genetically modified allergens are associated with reduced nasal allergen sensitivity. , 2005, The Journal of allergy and clinical immunology.

[159]  D. Bernstein,et al.  Onset and dose-related efficacy of house dust mite sublingual immunotherapy tablets in an environmental exposure chamber. , 2015, The Journal of allergy and clinical immunology.

[160]  P. Parren,et al.  Anti-Inflammatory Activity of Human IgG4 Antibodies by Dynamic Fab Arm Exchange , 2007, Science.

[161]  C. Mauri,et al.  Immune regulatory function of B cells. , 2012, Annual review of immunology.

[162]  S. Corrente,et al.  Dendritic cells modifi cation during sublingual immunotherapy in children with allergic symptoms to house dust mites , 2011, World journal of pediatrics : WJP.

[163]  T. Płusa,et al.  Cc‐chemokine eotaxin as a marker of efficacy of specific immunotherapy in patients with intermittent IgE‐mediated allergic rhinoconjunctivitis , 2003, Allergy.

[164]  Mengrong Li,et al.  Predictive Factors for Clinical Response to Allergy Immunotherapy in Children with Asthma and Rhinitis , 2014, International Archives of Allergy and Immunology.

[165]  J. Lamb,et al.  Impaired secretion of interleukin‐4 and interleukin‐13 by allergen‐specific T cells correlates with defective nuclear expression of NF‐AT2 and jun B: relevance to immunotherapy , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[166]  R. V. van Neerven,et al.  Blocking antibodies induced by specific allergy vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE-facilitated allergen presentation. , 1999, Journal of immunology.

[167]  L. Lichtenstein,et al.  Identification of basophil granulocytes as a site of allergic histamine release. , 1972, Journal of immunology.

[168]  H. Jansen,et al.  Monitoring human basophil activation via CD63 monoclonal antibody 435. , 1991, The Journal of allergy and clinical immunology.

[169]  J. Greenbaum,et al.  Association between specific timothy grass antigens and changes in TH1- and TH2-cell responses following specific immunotherapy. , 2014, The Journal of allergy and clinical immunology.

[170]  H. Malling,et al.  Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. , 2008, The Journal of allergy and clinical immunology.

[171]  K. Ozbilgin,et al.  Effects of allergen-specific immunotherapy on functions of helper and regulatory T cells in patients with seasonal allergic rhinitis. , 2011, European cytokine network.

[172]  Marek Jutel,et al.  IL‐10 and TGF‐β cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy , 2003, European journal of immunology.

[173]  L. Hothorn,et al.  Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. , 2012, The Journal of allergy and clinical immunology.

[174]  S. Durham,et al.  Grass Pollen Immunotherapy Induces an Allergen-Specific IgA2 Antibody Response Associated with Mucosal TGF-β Expression1 , 2007, The Journal of Immunology.

[175]  D. Robinson,et al.  Efficacy, safety, and immunological effects of a 2‐year immunotherapy with Depigoid® birch pollen extract: a randomized, double‐blind, placebo‐controlled study , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[176]  B. Bohle,et al.  Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. , 2007, The Journal of allergy and clinical immunology.

[177]  D. MacGlashan Expression of CD203c and CD63 in human basophils: relationship to differential regulation of piecemeal and anaphylactic degranulation processes , 2010, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[178]  R. Ėmužytė,et al.  Immunotherapy with depigmented‐polymerized mixed tree pollen extract: a clinical trial and responder analysis , 2010, Allergy.

[179]  T. Casale,et al.  Allergen immunotherapy: a new semantic framework from the European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report , 2013, Allergy.

[180]  T. Haahtela,et al.  Development of new IgE specificities to allergenic components in birch pollen extract during specific immunotherapy studied with immunoblotting and Pharmacia CAP System™ , 2002, Allergy.

[181]  S. Corrente,et al.  Dendritic cells modification during sublingual immunotherapy in children with allergic symptoms to house dust mites , 2022 .

[182]  J. Ceuppens,et al.  Immunotherapy with a modified birch pollen extract in allergic rhinoconjunctivitis: clinical and immunological effects , 2009, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[183]  Schlaak,et al.  Monitoring allergen immunotherapy of pollen‐allergic patients: the ratio of allergen‐specific IgG4 to IgG1 correlates with clinical outcome , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[184]  S. Durham,et al.  Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. , 2003, The Journal of allergy and clinical immunology.

[185]  S. Durham,et al.  Sublingual grass allergen tablet immunotherapy provides sustained clinical benefit with progressive immunologic changes over 2 years. , 2008, The Journal of allergy and clinical immunology.

[186]  M. Clerici,et al.  Immunological Effects of Sublingual Immunotherapy: Clinical Efficacy Is Associated with Modulation of Programmed Cell Death Ligand 1, IL-10, and IgG4 , 2010, The Journal of Immunology.

[187]  R. Valenta,et al.  Reduction in allergen-specific IgE binding as measured by microarray: A possible surrogate marker for effects of specific immunotherapy , 2015, The Journal of allergy and clinical immunology.

[188]  T. Rispens,et al.  Mechanism of immunoglobulin G4 Fab-arm exchange. , 2011, Journal of the American Chemical Society.

[189]  M. Blaiss,et al.  A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis , 2014, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[190]  M. Calderón,et al.  Allergen immunotherapy: clinical outcomes assessment. , 2014, The journal of allergy and clinical immunology. In practice.

[191]  J. Bousquet,et al.  Allergic rhinitis and its impact on asthma. , 2001, The Journal of allergy and clinical immunology.

[192]  R. Gerth van Wijk,et al.  Evaluation of Clinical and Immunological Responses: A 2-Year Follow-Up Study in Children with Allergic Rhinitis due to House Dust Mite , 2013, Mediators of Inflammation.

[193]  T. Casale,et al.  Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: the importance of allergen-specific serum IgE. , 2012, The Journal of allergy and clinical immunology.

[194]  Cezmi A Akdis,et al.  Mechanisms of allergen-specific immunotherapy and immune tolerance to allergens , 2015, The World Allergy Organization journal.

[195]  H. Malling,et al.  Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis. , 2007, The Journal of allergy and clinical immunology.

[196]  G. Passalacqua,et al.  Long‐term treatment with allergoid immunotherapy with Parietaria. Clinical and immunologic effects in a randomized, controlled trial , 1999, Allergy.