This article was originally published online on 15 June 2011In 1911 and long before the availability of antiallergic drugs, Leonard Noon demonstrated that prophylactic subcutaneous inoculation with a grass pollen extract was effective in suppressing immediate conjunctival sensitivity to grass pollen 1.Noon L. Prophylactic inoculation against hayfever.Lancet. 1911; 1: 1572Abstract Scopus (1110) Google Scholar. Noon's coworker, John Freeman, continued to practice immunotherapy and in 1930 published the first rush immunotherapy protocol 2.Freeman J. Rush inoculation with special reference to hay fever treatment.Lancet. 1930; 1: 744Abstract Scopus (84) Google Scholar. William Frankland, a colleague of Freeman, performed the first controlled clinical trial of grass pollen immunotherapy in 1954 3.Frankland A.W. Augustin R. Prophylaxis of summer hayfever and asthma: controlled trial comparing crude grass pollen extracts with isolated main protein component.Lancet. 1954; 1: 1055Abstract Scopus (230) Google Scholar. He used a whole grass pollen extract that was compared with its partially purified proteins, the corresponding ultrafiltrate that contained no protein and a phenol-containing diluent. Both the whole extract and the purified grass pollen proteins were effective compared with the ultrafiltrate and the diluent control alone (Fig. 1). Frankland's study established a firm scientific foundation for the practice of allergen immunotherapy. Noon, Freeman, and Frankland were all physicians at St. Mary's Hospital, Paddington, now affiliated to Imperial College London, United Kingdom. Frankland in his 99th year continues to practice and play a major role in the allergy community; much admired and respected by his colleagues, he represents our centenary link with the origins of the practice of immunotherapy (Fig. 2).Figure 2Dr. A. William Frankland in his 99th year, our centenary link with the origins of immunotherapy.View Large Image Figure ViewerDownload (PPT)Major advances in allergen immunotherapy have resulted from parallel studies performed in the United States. Lowell and Franklin in 1964 were the first to clearly demonstrate that a single allergen (ragweed) in a multiallergen mixture was effective in reducing seasonal allergic symptoms 4.Lowell F.C. Franklin W. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever.N Engl J Med. 1965; 273: 675-679Crossref PubMed Scopus (197) Google Scholar. Philip Norman and Larry Lichtenstein in 1978 convincingly demonstrated the allergen-specificity of ragweed immunotherapy in patients with dual sensitivity to ragweed and grass pollen 5.Norman P.S. Lichtenstein L.M. The clinical and immunologic specificity of immunotherapy.J Allergy Clin Immunol. 1978; 61: 370-377Abstract Full Text PDF PubMed Scopus (90) Google Scholar. Johnstone first highlighted the possibility that immunotherapy in children might confer protection against development of asthma, 6.Johnstone D.E. Dutton A. The value of hyposensitization therapy for bronchial asthma in children: a 14-year study.Pediatrics. 1968; 42: 793-802Crossref PubMed Google Scholar a concept supported by the more recent Preventive Allergy Treatment (PAT) study that identified a 2-3 fold risk reduction for developing asthma after 3 years treatment in children with seasonal pollinosis, protection that persisted for a further 7 years after discontinuation of immunotherapy 7.Jacobsen L. Niggemann B. Dreborg S. Ferdousi H.A. Halken S. et al.Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.Allergy. 2007; 62: 943-948Crossref PubMed Scopus (792) Google Scholar. Hunt and colleagues8.Hunt K.J. Valentine M.D. Sobotka A.K. Benton A.W. Amodio F.J. Lichtenstein L.M. A controlled trial of immunotherapy in insect hypersensitivity.N Engl J Med. 1978; 299: 157-161Crossref PubMed Scopus (591) Google Scholar demonstrated the efficacy of purified venom over whole insect body extract and placebo in patients with anaphylaxis to the stings of hymenoptera. Studies9.Nanda A. O'connor M. Anand M. Dreskin S.C. Zhang L. et al.Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract.J Allergy Clin Immunol. 2004; 114: 1339-1344Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar have confirmed the dose-dependency of allergen immunotherapy whereas the long-term benefits of allergen immunotherapy, with persistence of efficacy for several years after discontinuation10.Durham S.R. Walker S.M. Varga E.M. Jacobson M.R. et al.Long-term clinical efficacy of grass-pollen immunotherapy.N Engl J Med. 1999; 341: 468-475Crossref PubMed Scopus (1246) Google Scholar have been illustrated for both venom11.Golden D.B. Kagey-Sobotka A. Lichtenstein L.M. Survey of patients after discontinuing venom immunotherapy.J Allergy Clin Immunol. 2000; 105: 385-390Abstract Full Text Full Text PDF PubMed Google Scholar and grass pollen immunotherapy, the latter both for subcutaneous and sublingual routes of therapy 12.Durham S.R. Emminger W. Kapp A. Colombo G. de Monchy J.G. et al.Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet.J Allergy Clin Immunol. 2010; 125: 131-138Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar.Our increasing knowledge of the mechanisms of immunotherapy has informed both novel approaches and the development of putative biomarkers that might predict the clinical response to immunotherapy. Prausnitz and Kustner13.Prausnitz C. Küstner H. Studien über die Ueberempfindlichkeit.Zentralbl Bakteriol. 1921; 86: 160-169Google Scholar published in 1921 that a serum factor ('reagin') could transfer immediate allergen sensitivity as shown by skin testing was followed Robert Cooke's observation in 1935 that serum obtained after pollen immunotherapy could confer 'immunity and hypersensitivity.'14.Cooke R.A. Barnard J.H. Hebald S. Stull A. Serological immunity with co-existing sensitisation in a type of human allergy (hay fever).J Exp Med. 1935; 62: 733Crossref PubMed Scopus (251) Google Scholar These seminal observations long preceded the discovery of IgE antibody as reagin by the Ishizakas, 15.Ishizaka K. Ishizaka T. Hornbrook M.M. Physiochemical properties of reaginic antibody V. Correlation of reaginic activity with yEglobulin antibody.J Immunol. 1966; 97: 840PubMed Google Scholar Johansson and Bennich, 16.Johansson SGO, Bennich H: Studies On a New Class of Human Immunoglobulins. 1. Immunological Properties. Nobel Symposium 3, Gamma Globulins, Structure and Control of Biosynthesis. Almqvist and Wiksell: Stockholm, 193-Google Scholar and the concept of IgG 'blocking antibodies.'17.Gleich G.J. Zimmermann E.M. Henderson L.L. Yunginger J.W. Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.J Allergy Clin Immunol. 1982; 70: 261-271Abstract Full Text PDF PubMed Scopus (233) Google Scholar The suppressive effect of ragweed immunotherapy on nasal eosinophils as a local marker of allergic inflammation was shown by Creticos in 1984, 18.Shamji M.H. Wilcock L.K. Wachholz P.A. Dearman R.J. Kimber I. et al.The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses.J Immunol Methods. 2006; 17: 71-79Crossref Scopus (115) Google Scholar whereas Passalacqua and Canonica similarly demonstrated decreased local eosinophilia and adhesion molecule expression during mite sublingual immunotherapy 19.Creticos P.S. Marsh D.G. Proud D. Kagey-Sobotka A. Adkinson Jr, N.F. et al.Responses to ragweed-pollen nasal challenge before and after immunotherapy.J Allergy Clin Immunol. 1989; 84: 197-205Abstract Full Text PDF PubMed Scopus (96) Google Scholar. Warner in 197820.Passalacqua G. Albano M. Fregonese L. Riccio A. Pronzato C. Mela G.S. Canonica G.W. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis.Lancet. 1998; 28:351: 629-632Google Scholar and Rak21.Warner J.O. Price J.F. Soothill J.F. Hey E.N. Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma.Lancet. 1978; 28:2: 912-915Abstract Scopus (282) Google Scholar in 1991 observed decreases in allergen-induced late asthmatic responses and associated bronchial inflammation, respectively, in children and adults. A link between altered T-cell responses and immunotherapy was first shown by Rocklin22.Rak S. Björnson A. Håkanson L. Sörenson S. Venge P. The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure.J Allergy Clin Immunol. 1991; 88: 878-888Abstract Full Text PDF PubMed Scopus (118) Google Scholar whereas the critical role of regulatory T cells and IL-10 was highlighted by Akdis and colleagues 23.Rocklin R.E. Sheffer A.L. Greineder D.K. Melmon K.L. Generation of antigen-specific suppressor cells during allergy desensitization.N Engl J Med. 1980; 302: 1213-1219Crossref PubMed Scopus (262) Google Scholar. The concept of immune deviation of allergen-specific TH2 responses in favor of TH1 responses in both the periphery and in target organs has developed in parallel 24.Akdis C.A. Blesken T. Akdis M. Wüthrich B. Blaser K. Role of interleukin 10 in specific immunothera.J Clin Invest. 1998; 1021: 98-106Crossref Scopus (883) Google Scholar, 25.Varney V.A. Hamid Q.A. Gaga M. Ying S. Jacobson M. Frew A.J. Kay A.B. Durham S.R. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.J Clin Invest. 1993; 92: 644-651Crossref PubMed Scopus (470) Google Scholar–26.Ebner C. Siemann U. Bohle B. Willheim M. Wiedermann U. 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 Phl p 1, a major grass pollen allergen.Clin Exp Allergy. 1997; 27: 1007-1015Crossref PubMed Scopus (315) Google Scholar.It is paradoxical that 100 years on we continue to use conventional high-dose subcutaneous injection immunotherapy with allergen extracts as gold standard therapy. A key question remains whether either B cell and/or T cell epitopes expressed by allergens are necessary singly or together for successful immunotherapy. Whether T-cell focused therapies alone are sufficient is currently being tested in the context of T-cell peptide immunotherapy 27.Durham S.R. Ying S. Varney V.A. Jacobson M.R. Sudderick R.M. Mackay I.S. Kay A.B. Hamid Q.A. 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.J Allergy Clin Immunol. 1996; 97: 1356-1365Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 28.Norman P.S. Ohman Jr, J.L. Long A.A. Creticos P.S. Gefter M.A. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar. Other novel approaches such as the focus on adjuvants in combination with allergens, 29.Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Feld1on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 30.Tulic M.K. Fiset P.O. Christodoulopoulos P. Vaillancourt P. Desrosiers M. Lavigne F. Eiden J. Hamid Q. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response.J Allergy Clin Immunol. 2004; 113: 235-241Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar alternative routes of administration (sublingual, 31.Creticos P.S. Schroeder J.T. Hamilton R.G. Balcer-Whaley S.L. Khattignavong A.P. et al.Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.N Engl J Med. 2006; 355: 1445-1455Crossref PubMed Scopus (499) Google Scholar transdermal, 32.Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011. doi:10.1111/j.1398–9995.2011.02583.xGoogle Scholar intranodal33.Senti G. Graf N. Haug S. Rüedi N. von Moos S. Sonderegger T. Johansen P. Kündig T.M. Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy.J Allergy Clin Immunol. 2009; 124: 997-1002Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar) and the use of recombinant allergens and their hypo-allergenic variants34.Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer.Proc Natl Acad Sci. 2008; 105: 17908-17912Crossref PubMed Scopus (262) Google Scholar are all currently being tested in phase II-III trials.These novel strategies will hopefully augment efficacy while improving the safety of immunotherapy, thereby making immunotherapy more broadly available to allergy sufferers, including patients with more severe allergic asthma. Further confirmation that immunotherapy has potential to induce remission and prevent progression of allergic disease should attract earlier interventions in children and young adults who are the group who may potentially benefit most from this disease-modifying treatment. This article was originally published online on 15 June 2011 In 1911 and long before the availability of antiallergic drugs, Leonard Noon demonstrated that prophylactic subcutaneous inoculation with a grass pollen extract was effective in suppressing immediate conjunctival sensitivity to grass pollen 1.Noon L. Prophylactic inoculation against hayfever.Lancet. 1911; 1: 1572Abstract Scopus (1110) Google Scholar. Noon's coworker, John Freeman, continued to practice immunotherapy and in 1930 published the first rush immunotherapy protocol 2.Freeman J. Rush inoculation with special reference to hay fever treatment.Lancet. 1930; 1: 744Abstract Scopus (84) Google Scholar. William Frankland, a colleague of Freeman, performed the first controlled clinical trial of grass pollen immunotherapy in 1954 3.Frankland A.W. Augustin R. Prophylaxis of summer hayfever and asthma: controlled trial comparing crude grass pollen extracts with isolated main protein component.Lancet. 1954; 1: 1055Abstract Scopus (230) Google Scholar. He used a whole grass pollen extract that was compared with its partially purified proteins, the corresponding ultrafiltrate that contained no protein and a phenol-containing diluent. Both the whole extract and the purified grass pollen proteins were effective compared with the ultrafiltrate and the diluent control alone (Fig. 1). Frankland's study established a firm scientific foundation for the practice of allergen immunotherapy. Noon, Freeman, and Frankland were all physicians at St. Mary's Hospital, Paddington, now affiliated to Imperial College London, United Kingdom. Frankland in his 99th year continues to practice and play a major role in the allergy community; much admired and respected by his colleagues, he represents our centenary link with the origins of the practice of immunotherapy (Fig. 2). Major advances in allergen immunotherapy have resulted from parallel studies performed in the United States. Lowell and Franklin in 1964 were the first to clearly demonstrate that a single allergen (ragweed) in a multiallergen mixture was effective in reducing seasonal allergic symptoms 4.Lowell F.C. Franklin W. A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever.N Engl J Med. 1965; 273: 675-679Crossref PubMed Scopus (197) Google Scholar. Philip Norman and Larry Lichtenstein in 1978 convincingly demonstrated the allergen-specificity of ragweed immunotherapy in patients with dual sensitivity to ragweed and grass pollen 5.Norman P.S. Lichtenstein L.M. The clinical and immunologic specificity of immunotherapy.J Allergy Clin Immunol. 1978; 61: 370-377Abstract Full Text PDF PubMed Scopus (90) Google Scholar. Johnstone first highlighted the possibility that immunotherapy in children might confer protection against development of asthma, 6.Johnstone D.E. Dutton A. The value of hyposensitization therapy for bronchial asthma in children: a 14-year study.Pediatrics. 1968; 42: 793-802Crossref PubMed Google Scholar a concept supported by the more recent Preventive Allergy Treatment (PAT) study that identified a 2-3 fold risk reduction for developing asthma after 3 years treatment in children with seasonal pollinosis, protection that persisted for a further 7 years after discontinuation of immunotherapy 7.Jacobsen L. Niggemann B. Dreborg S. Ferdousi H.A. Halken S. et al.Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.Allergy. 2007; 62: 943-948Crossref PubMed Scopus (792) Google Scholar. Hunt and colleagues8.Hunt K.J. Valentine M.D. Sobotka A.K. Benton A.W. Amodio F.J. Lichtenstein L.M. A controlled trial of immunotherapy in insect hypersensitivity.N Engl J Med. 1978; 299: 157-161Crossref PubMed Scopus (591) Google Scholar demonstrated the efficacy of purified venom over whole insect body extract and placebo in patients with anaphylaxis to the stings of hymenoptera. Studies9.Nanda A. O'connor M. Anand M. Dreskin S.C. Zhang L. et al.Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract.J Allergy Clin Immunol. 2004; 114: 1339-1344Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar have confirmed the dose-dependency of allergen immunotherapy whereas the long-term benefits of allergen immunotherapy, with persistence of efficacy for several years after discontinuation10.Durham S.R. Walker S.M. Varga E.M. Jacobson M.R. et al.Long-term clinical efficacy of grass-pollen immunotherapy.N Engl J Med. 1999; 341: 468-475Crossref PubMed Scopus (1246) Google Scholar have been illustrated for both venom11.Golden D.B. Kagey-Sobotka A. Lichtenstein L.M. Survey of patients after discontinuing venom immunotherapy.J Allergy Clin Immunol. 2000; 105: 385-390Abstract Full Text Full Text PDF PubMed Google Scholar and grass pollen immunotherapy, the latter both for subcutaneous and sublingual routes of therapy 12.Durham S.R. Emminger W. Kapp A. Colombo G. de Monchy J.G. et al.Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet.J Allergy Clin Immunol. 2010; 125: 131-138Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar. Our increasing knowledge of the mechanisms of immunotherapy has informed both novel approaches and the development of putative biomarkers that might predict the clinical response to immunotherapy. Prausnitz and Kustner13.Prausnitz C. Küstner H. Studien über die Ueberempfindlichkeit.Zentralbl Bakteriol. 1921; 86: 160-169Google Scholar published in 1921 that a serum factor ('reagin') could transfer immediate allergen sensitivity as shown by skin testing was followed Robert Cooke's observation in 1935 that serum obtained after pollen immunotherapy could confer 'immunity and hypersensitivity.'14.Cooke R.A. Barnard J.H. Hebald S. Stull A. Serological immunity with co-existing sensitisation in a type of human allergy (hay fever).J Exp Med. 1935; 62: 733Crossref PubMed Scopus (251) Google Scholar These seminal observations long preceded the discovery of IgE antibody as reagin by the Ishizakas, 15.Ishizaka K. Ishizaka T. Hornbrook M.M. Physiochemical properties of reaginic antibody V. Correlation of reaginic activity with yEglobulin antibody.J Immunol. 1966; 97: 840PubMed Google Scholar Johansson and Bennich, 16.Johansson SGO, Bennich H: Studies On a New Class of Human Immunoglobulins. 1. Immunological Properties. Nobel Symposium 3, Gamma Globulins, Structure and Control of Biosynthesis. Almqvist and Wiksell: Stockholm, 193-Google Scholar and the concept of IgG 'blocking antibodies.'17.Gleich G.J. Zimmermann E.M. Henderson L.L. Yunginger J.W. Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.J Allergy Clin Immunol. 1982; 70: 261-271Abstract Full Text PDF PubMed Scopus (233) Google Scholar The suppressive effect of ragweed immunotherapy on nasal eosinophils as a local marker of allergic inflammation was shown by Creticos in 1984, 18.Shamji M.H. Wilcock L.K. Wachholz P.A. Dearman R.J. Kimber I. et al.The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses.J Immunol Methods. 2006; 17: 71-79Crossref Scopus (115) Google Scholar whereas Passalacqua and Canonica similarly demonstrated decreased local eosinophilia and adhesion molecule expression during mite sublingual immunotherapy 19.Creticos P.S. Marsh D.G. Proud D. Kagey-Sobotka A. Adkinson Jr, N.F. et al.Responses to ragweed-pollen nasal challenge before and after immunotherapy.J Allergy Clin Immunol. 1989; 84: 197-205Abstract Full Text PDF PubMed Scopus (96) Google Scholar. Warner in 197820.Passalacqua G. Albano M. Fregonese L. Riccio A. Pronzato C. Mela G.S. Canonica G.W. Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis.Lancet. 1998; 28:351: 629-632Google Scholar and Rak21.Warner J.O. Price J.F. Soothill J.F. Hey E.N. Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma.Lancet. 1978; 28:2: 912-915Abstract Scopus (282) Google Scholar in 1991 observed decreases in allergen-induced late asthmatic responses and associated bronchial inflammation, respectively, in children and adults. A link between altered T-cell responses and immunotherapy was first shown by Rocklin22.Rak S. Björnson A. Håkanson L. Sörenson S. Venge P. The effect of immunotherapy on eosinophil accumulation and production of eosinophil chemotactic activity in the lung of subjects with asthma during natural pollen exposure.J Allergy Clin Immunol. 1991; 88: 878-888Abstract Full Text PDF PubMed Scopus (118) Google Scholar whereas the critical role of regulatory T cells and IL-10 was highlighted by Akdis and colleagues 23.Rocklin R.E. Sheffer A.L. Greineder D.K. Melmon K.L. Generation of antigen-specific suppressor cells during allergy desensitization.N Engl J Med. 1980; 302: 1213-1219Crossref PubMed Scopus (262) Google Scholar. The concept of immune deviation of allergen-specific TH2 responses in favor of TH1 responses in both the periphery and in target organs has developed in parallel 24.Akdis C.A. Blesken T. Akdis M. Wüthrich B. Blaser K. Role of interleukin 10 in specific immunothera.J Clin Invest. 1998; 1021: 98-106Crossref Scopus (883) Google Scholar, 25.Varney V.A. Hamid Q.A. Gaga M. Ying S. Jacobson M. Frew A.J. Kay A.B. Durham S.R. Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses.J Clin Invest. 1993; 92: 644-651Crossref PubMed Scopus (470) Google Scholar–26.Ebner C. Siemann U. Bohle B. Willheim M. Wiedermann U. 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 Phl p 1, a major grass pollen allergen.Clin Exp Allergy. 1997; 27: 1007-1015Crossref PubMed Scopus (315) Google Scholar. It is paradoxical that 100 years on we continue to use conventional high-dose subcutaneous injection immunotherapy with allergen extracts as gold standard therapy. A key question remains whether either B cell and/or T cell epitopes expressed by allergens are necessary singly or together for successful immunotherapy. Whether T-cell focused therapies alone are sufficient is currently being tested in the context of T-cell peptide immunotherapy 27.Durham S.R. Ying S. Varney V.A. Jacobson M.R. Sudderick R.M. Mackay I.S. Kay A.B. Hamid Q.A. 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.J Allergy Clin Immunol. 1996; 97: 1356-1365Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar, 28.Norman P.S. Ohman Jr, J.L. Long A.A. Creticos P.S. Gefter M.A. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar. Other novel approaches such as the focus on adjuvants in combination with allergens, 29.Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Feld1on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 30.Tulic M.K. Fiset P.O. Christodoulopoulos P. Vaillancourt P. Desrosiers M. Lavigne F. Eiden J. Hamid Q. Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response.J Allergy Clin Immunol. 2004; 113: 235-241Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar alternative routes of administration (sublingual, 31.Creticos P.S. Schroeder J.T. Hamilton R.G. Balcer-Whaley S.L. Khattignavong A.P. et al.Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.N Engl J Med. 2006; 355: 1445-1455Crossref PubMed Scopus (499) Google Scholar transdermal, 32.Radulovic S, Wilson D, Calderon M, Durham S. Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011. doi:10.1111/j.1398–9995.2011.02583.xGoogle Scholar intranodal33.Senti G. Graf N. Haug S. Rüedi N. von Moos S. Sonderegger T. Johansen P. Kündig T.M. Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy.J Allergy Clin Immunol. 2009; 124: 997-1002Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar) and the use of recombinant allergens and their hypo-allergenic variants34.Senti G. Prinz Vavricka B.M. Erdmann I. Diaz M.I. Markus R. et al.Intralymphatic allergen administration renders specific immunotherapy faster and safer.Proc Natl Acad Sci. 2008; 105: 17908-17912Crossref PubMed Scopus (262) Google Scholar are all currently being tested in phase II-III trials. These novel strategies will hopefully augment efficacy while improving the safety of immunotherapy, thereby making immunotherapy more broadly available to allergy sufferers, including patients with more severe allergic asthma. Further confirmation that immunotherapy has potential to induce remission and prevent progression of allergic disease should attract earlier interventions in children and young adults who are the group who may potentially benefit most from this disease-modifying treatment.