- Notes of allergy watchers
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Allergen Immunotherapy: A Centenary Celebration
World Allergy Organization Journal volume 4, pages 104–106 (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's coworker, John Freeman, continued to practice immunotherapy and in 1930 published the first rush immunotherapy protocol [2]. William Frankland, a colleague of Freeman, performed the first controlled clinical trial of grass pollen immunotherapy in 1954 [3]. 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 (Figure 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 (Figure 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]. 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]. Johnstone first highlighted the possibility that immunotherapy in children might confer protection against development of asthma, [6] 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]. Hunt and colleagues[8] demonstrated the efficacy of purified venom over whole insect body extract and placebo in patients with anaphylaxis to the stings of hymenoptera. Studies[9] have confirmed the dose-dependency of allergen immunotherapy whereas the long-term benefits of allergen immunotherapy, with persistence of efficacy for several years after discontinuation[10] have been illustrated for both venom[11] and grass pollen immunotherapy, the latter both for subcutaneous and sublingual routes of therapy [12].
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 Kustner[13] 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] These seminal observations long preceded the discovery of IgE antibody as reagin by the Ishizakas, [15] Johansson and Bennich, [16] and the concept of IgG 'blocking antibodies.'[17] The suppressive effect of ragweed immunotherapy on nasal eosinophils as a local marker of allergic inflammation was shown by Creticos in 1984, [18] whereas Passalacqua and Canonica similarly demonstrated decreased local eosinophilia and adhesion molecule expression during mite sublingual immunotherapy [19]. Warner in 1978[20] and Rak[21] 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 Rocklin[22] whereas the critical role of regulatory T cells and IL-10 was highlighted by Akdis and colleagues [23]. 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 [24–26].
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, 28]. Other novel approaches such as the focus on adjuvants in combination with allergens, [29, 30] alternative routes of administration (sublingual, [31] transdermal, [32] intranodal[33]) and the use of recombinant allergens and their hypo-allergenic variants[34] 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.
References
Noon L: Prophylactic inoculation against hayfever. Lancet. 1911, 1: 1572-
Freeman J: Rush inoculation with special reference to hay fever treatment. Lancet. 1930, 1: 744-
Frankland AW, Augustin R: Prophylaxis of summer hayfever and asthma: controlled trial comparing crude grass pollen extracts with isolated main protein component. Lancet. 1954, 1: 1055-
Lowell FC, Franklin W: A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N Engl J Med. 1965, 273: 675-679. 10.1056/NEJM196509232731302.
Norman PS, Lichtenstein LM: The clinical and immunologic specificity of immunotherapy. J Allergy Clin Immunol. 1978, 61: 370-377. 10.1016/0091-6749(78)90116-1.
Johnstone DE, Dutton A: The value of hyposensitization therapy for bronchial asthma in children: a 14-year study. Pediatrics. 1968, 42: 793-802.
Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, 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: 943-948. 10.1111/j.1398-9995.2007.01451.x.
Hunt KJ, Valentine MD, Sobotka AK, Benton AW, Amodio FJ, Lichtenstein LM: A controlled trial of immunotherapy in insect hypersensitivity. N Engl J Med. 1978, 299: 157-161. 10.1056/NEJM197807272990401.
Nanda A, O'connor M, Anand M, Dreskin SC, 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: 1339-1344. 10.1016/j.jaci.2004.08.049.
Durham SR, Walker SM, Varga EM, Jacobson MR, et al: Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999, 341: 468-475. 10.1056/NEJM199908123410702.
Golden DB, Kagey-Sobotka A, Lichtenstein LM: Survey of patients after discontinuing venom immunotherapy. J Allergy Clin Immunol. 2000, 105 (2 Pt 1): 385-390.
Durham SR, Emminger W, Kapp A, Colombo G, de Monchy JG, 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: 131-138. 10.1016/j.jaci.2009.10.035.
Prausnitz C, Küstner H: Studien über die Ueberempfindlichkeit. Zentralbl Bakteriol. 1921, 86: 160-169.
Cooke RA, Barnard JH, Hebald S, Stull A: Serological immunity with co-existing sensitisation in a type of human allergy (hay fever). J Exp Med. 1935, 62: 733-10.1084/jem.62.6.733.
Ishizaka K, Ishizaka T, Hornbrook MM: Physiochemical properties of reaginic antibody V. Correlation of reaginic activity with yEglobulin antibody. J Immunol. 1966, 97: 840-
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-
Gleich GJ, Zimmermann EM, Henderson LL, Yunginger JW: Effect of immunotherapy on immunoglobulin E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study. J Allergy Clin Immunol. 1982, 70: 261-271. 10.1016/0091-6749(82)90062-8.
Shamji MH, Wilcock LK, Wachholz PA, Dearman RJ, 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: 71-79.
Creticos PS, Marsh DG, Proud D, Kagey-Sobotka A, Adkinson NF, et al: Responses to ragweed-pollen nasal challenge before and after immunotherapy. J Allergy Clin Immunol. 1989, 84: 197-205. 10.1016/0091-6749(89)90325-4.
Passalacqua G, Albano M, Fregonese L, Riccio A, Pronzato C, Mela GS, Canonica GW: Randomised controlled trial of local allergoid immunotherapy on allergic inflammation in mite-induced rhinoconjunctivitis. Lancet. 1998, 28:351: 629-632.
Warner JO, Price JF, Soothill JF, Hey EN: Controlled trial of hyposensitisation to Dermatophagoides pteronyssinus in children with asthma. Lancet. 1978, 28:2: 912-915.
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: 878-888. 10.1016/0091-6749(91)90244-I.
Rocklin RE, Sheffer AL, Greineder DK, Melmon KL: Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med. 1980, 302: 1213-1219. 10.1056/NEJM198005293022201.
Akdis CA, Blesken T, Akdis M, Wüthrich B, Blaser K: Role of interleukin 10 in specific immunothera. J Clin Invest. 1998, 1021: 98-106.
Varney VA, Hamid QA, Gaga M, Ying S, Jacobson M, Frew AJ, Kay AB, Durham SR: Influence of grass pollen immunotherapy on cellular infiltration and cytokine mRNA expression during allergen-induced late-phase cutaneous responses. J Clin Invest. 1993, 92: 644-651. 10.1172/JCI116633.
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: 1007-1015. 10.1111/j.1365-2222.1997.tb01252.x.
Durham SR, Ying S, Varney VA, Jacobson MR, Sudderick RM, Mackay IS, Kay AB, Hamid QA: 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: 1356-1365. 10.1016/S0091-6749(96)70205-1.
Norman PS, Ohman JL, Long AA, Creticos PS, Gefter MA, et al: Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med. 1996, 154: 1623-1628. 10.1164/ajrccm.154.6.8970345.
Oldfield WL, Larche M, Kay AB: 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: 47-53. 10.1016/S0140-6736(02)09332-7.
Tulic MK, Fiset PO, 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: 235-241. 10.1016/j.jaci.2003.11.001.
Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, et al: Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006, 355: 1445-1455. 10.1056/NEJMoa052916.
Radulovic S, Wilson D, Calderon M, Durham S: Systematic reviews of sublingual immunotherapy (SLIT). Allergy. 2011, doi:10.1111/j.1398-9995.2011.02583.x
Senti G, Graf N, Haug S, Rüedi N, von Moos S, Sonderegger T, Johansen P, Kündig TM: Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy. J Allergy Clin Immunol. 2009, 124: 997-1002. 10.1016/j.jaci.2009.07.019.
Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, et al: Intralymphatic allergen administration renders specific immunotherapy faster and safer. Proc Natl Acad Sci. 2008, 105: 17908-17912. 10.1073/pnas.0803725105.
Valenta R, Ferreira F, Focke-Tejkl M, Linhart B, Niederberger V, Swoboda I, Vrtala S: From allergen genes to allergy vaccines. Annu Rev Immunol. 2010, 28: 211-241. 10.1146/annurev-immunol-030409-101218.
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Durham, S.R., Nelson, H. Allergen Immunotherapy: A Centenary Celebration. World Allergy Organ J 4, 104–106 (2011). https://doi.org/10.1097/WOX.0b013e3182218920
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DOI: https://doi.org/10.1097/WOX.0b013e3182218920