Posted by: Indonesian Children | April 6, 2010



An update on subcutaneous immunotherapy, other routes of immunotherapy administration, different allergens and impact of immunotherapy on the natural history of disease.

  • Many double-blind, placebo-controlled studies confirm the efficacy of subcutaneous immunotherapy for treatment of allergic rhinitis, allergic asthma, and Hymenoptera venom hypersensitivity.
  • Studies are lacking that support immunotherapy with fungal extracts, other than for Alternaria and Cladosporium, and with cockroach extracts.
  • Although limited in number, some controlled studies have demonstrated efficacy of subcutaneous immunotherapy with multiple allergen mixes. However, there have also been negative studies.
  • There seem to be 2 distinct and perhaps sequential immunologic responses to immunotherapy, generation of regulatory T-cells (T regs) secreting interleukin (IL)-10 and transforming growth factor (TGF)-β and immune deviation from TH2 to TH1 responses.
  • Subcutaneous immunotherapy has reduced the development of new sensitizations in monosensitized patients and, in a few studies, has reduced the development of asthma in children who only have allergic rhinitis.
  • The beneficial effects of subcutaneous immunotherapy persist for years after discontinuation.
  • The use of subcutaneous immunotherapy is limited by the occurrence of local and systemic reactions (SRs) and the prolonged period required for build-up to maintenance dosing.


Historical Development

Subcutaneous administration of increasing doses of a grass-pollen extract to treat allergic rhinitis was introduced by Leonard Noon in 1911,1 with completion of his studies by John Freeman.2 Timothy grass was administered preseasonally or seasonally. This treatment was subsequently extended to other seasonal and perennial allergens and to the treatment of allergic asthma and rhinitis.3 Perennial administration largely replaced preseasonal treatment. While immunotherapy was initially used based on the clinical impression of efficacy, in the 1960s, definitive double-blind studies using ragweed pollen extract established that this was an effective form of treatment.4,5

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Clinical Efficacy

Many double-blind, placebo-controlled studies confirm the efficacy of subcutaneous injection allergen specific immunotherapy (SCIT) for treatment of both allergic rhinitis6 and allergic asthma.7 These studies showed efficacy with extracts of various pollens, animal danders, HDMs, and fungi. For most classes of allergens, results support efficacy. However, although a few small size studies report positive results treating patients with Cladosporium8 and Alternaria,9 studies supporting immunotherapy with many of the other available fungal allergen extracts are lacking.10

Most controlled studies included in SCIT meta-analyses that show clinical efficacy of SCIT for allergic rhinitis and asthma include only a single allergen extract. Although there are controlled studies that demonstrate efficacy for multiple allergen mixes for treatment of both allergic rhinitis4 and allergic asthma,11 the studies are more than 40 years old and there are no recent studies.

Mechanisms of Action

Along with evidence of the efficacy has come an understanding of the probable mechanisms by which SCIT alters the disease processes. The earliest objective evidence of an immune response was the observation by Noon that immunotherapy reduced conjunctival sensitivity to timothy grass extract.1 Subsequent observations confirm a reduction of sensitivity to the injected allergen in the skin, or topical allergen on the conjunctivae, nasal mucosa and lungs.12,13 Humoral responses were also observed, with first an increase and later a decline in specific immunoglobin(Ig)E14 and the generation of a blocking IgG antibody.15 However, studies failed to correlate these responses with clinical improvement.16

Research today is focused on changes in T-lymphocyte responses and 2 distinct patterns of change, which may occur sequentially. An event that occurs within 7 days at high allergen doses17 and 2–4 weeks at low allergen doses18,19 is the generation of regulatory T-cells secreting IL-10 and TGF-β19 accompanied by suppression of allergen-induced late cutaneous responses.17,18 This is followed at 6–12 weeks after initiating therapy by corresponding elevations in allergen-specific IgG4 and IgA that parallel a more delayed suppression of allergen-induced early cutaneous responses.18,19 A second and probably later immunologic response is immune deviation with a shift in the allergen specific T-cell response from predominantly TH2 to TH1.20

Impact on Natural History

Considering the profound effect on the immune response to the administered allergen, it is not surprising that SCIT alters the natural course of allergic diseases. Several studies have demonstrated that SCIT, when administered to monosensitized patients, reduces the likelihood of developing new sensitivities.21–23 Furthermore, the reduction in new sensitivities persists for at least 3 years after discontinuation of treatment.22,23 A similar inhibitory effect occurs for the progression to asthma in children suffering from only allergic rhinitis.24 Timothy or birch pollen SCIT reduced the development of new onset asthma during the course of 3 years of treatment25 and reduced the incidence of asthma with little loss of effect more than 7 years of posttreatment observation. The beneficial effects of SCIT on allergy symptoms persist for years after its discontinuation. In a prospective, placebo-controlled trial, subjects who discontinued timothy grass SCIT after 3 to 4 years of treatment had the same level of symptoms during the next 3 grass pollen seasons as did the group who continued on monthly maintenance injections.26

Alternative Approaches to Immunotherapy

Despite its clinical and disease-modifying efficacy, SCIT has some disadvantages: it is not ‘patient friendly’ because of the regular injections, which may arouse fear among children and some adults, and it has some indirect costs such as travel to the doctor’s office and lost work/school hours. The use of SCIT is also limited by the prolonged time for build-up required to reach maintenance levels of treatment and by adverse reactions. Attempts to improve the former have lead to trials with accelerated treatment schedules, while the latter has been addressed by modifying the allergen extracts or administering them by routes other than injection. Alternatives to the weekly build-up include administering clusters of 2 or 3 injections, usually 30 minutes apart, during a single clinic visit with visits spread over several weeks.27 This cluster schedule is not associated with an increased incidence of adverse reactions.28 However, a more rapid build-up, in which maintenance is achieved in just one or a few days, is associated with an increased incidence of reactions even when treatment subjects are premedicated.29 Extract modification includes adsorption of the extract to aluminum to achieve a depot effect30 and modifying the extracts with formaldehyde31 or glutaraldehyde32 to reduce reactivity with specific IgE. Recombinant technology is currently being used to produce altered proteins33 or peptides34,35 that retain T-cell epitopes but are no longer recognized by the specific IgE. Another approach is to combine the allergen with products, most extensively with monophosphoryl lipid A36 or CpG motifs,37 that stimulate the innate immune system thereby favoring a TH1 response.

Another approach is to administer the extracts by an alternative route, for example, orally38 or sublingually39 slowing absorption and presenting the extract to a different component of the immune system. Other alternative approaches are to administer the extract directly on to the respiratory mucosa, either into the upper or lower respiratory tracts.40,41 This approach can induce allergic respiratory symptoms, therefore, either modified extracts with decreased allergenicity are used42 or cromolyn sodium is applied to the mucosa before the allergen is administered to block the allergic reaction.43

  1. Noon L. Prophylactic inoculation against hay fever. Lancet. 1911;i:1572–1573. Cited Here…
  2. Freeman J. Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine. Lancet. 1911;ii:814–817. Cited Here…
  3. Cohen SG, Evans R III. Allergen Immunotherapy in Historical Perspective. In: Lockey RF, Ledford DK, eds. Allergens and Allergen Immunotherapy. 4th ed. New York: Informa Healthcare, 2008;1–29. Cited Here…
  4. 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. Cited Here…
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  8. Malling H-J, Dreborg S, Weeke B. Diagnosis and immunotherapy of mould allergy. V. Clinical efficacy and side effects of immunotherapy with Cladosporium herbarum. Allergy. 1986;41:507–519. Cited Here… | PubMed | CrossRef
  9.  Horst M, Hejjaoui A, Horst V, Michel B, Bousquet J. Double-blind, placebo-controlled rush immunotherapy with a standardized Alternaria extract. J Allergy Clin Immunol. 1990;85 460–472.Cited Here… | PubMed | CrossRef
  10.  Salvaggio JE, Burge HA, Chapman JA. Emerging concepts in mold allergy: what is the role of immunotherapy. J Allergy Clin Immunol. 1993;92:217–222.Cited Here… | PubMed | CrossRef
  11.  Johnstone DE, Crump L. Value of hyposensitization therapy for perennial bronchial asthma in children. Pediatrics. 1961;27:39–44.Cited Here… | PubMed
  12.  Bousquet J, Maasch H, Martinot B, Heijaoui A, Wahl R, et al. Double-blind, placebo-controlled immunotherapy with mixed grass pollen allergoids. II. Comparison between parameters assessing the efficacy of immunotherapy. J Allergy Clin Immunol. 1988;82:439–446.Cited Here… | PubMed | CrossRef
  13.  Hedlin G, Graf-Lonnevig L, Heilbron H, et al. Immunotherapy with cat and dog dander extracts: V. Effects of three years of treatment. J Allergy Clin Immunol. 1991;87:955–964.Cited Here… | PubMed | CrossRef
  14. WB, Stull A, Cooke RA. Serologic changes in hay fever cases treated over a period of years. J Allergy. 1940;11:225–244.Cited Here… | CrossRef
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  18. Francis JN, James LK, Paraskevopoulos G, Wong C, Calderon MA, et al. Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol. 2008;121:1120–1125.Cited Here… | PubMed | CrossRef
  19.  Jutel M, Akdis M, Budak F, Aebischer-Casaulter C, Wrzyszcz M, et al. IL-10 and TGF-β cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003;33:1205–1214.Cited Here… | PubMed | CrossRef
  20. Hamid QA, Schotman E, Jacobson MR, Walker SM, Durham SR. Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J Allergy Clin Immunol. 1997;99:254–260.Cited Here… | PubMed | CrossRef
  21. Des Roches A, Paradis L, Menardo J-L, Bouges S, Daurés JP, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J Allergy Clin Immunol. 1997;99:450–453.Cited Here… | PubMed
  22. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A Six-year follow-up study. Clin Exp Allergy. 2001;31:1392–1397.Cited Here… | View Full Text | PubMed | CrossRef
  23. Purello-D’Ambrosio F, Gangemi S, Merendino RA, Isola S, Puccinelli P, Parmiani S, Ricciardi L. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy. 2001;31:1295–1302.Cited Here… | View Full Text | PubMed | CrossRef
  24. Jacobsen L, Niggemann B, Dreborg S, Ferdousi HA, Halken S, et al. Specific immunotherapy has long-term preventive effect on seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy. 2007;62:943–948.Cited Here… | View Full Text | PubMed | CrossRef
  25. Moller C, Dreborg S, Ferdousi HA, Halken S, Host A, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol. 2002;109:251–256.Cited Here…
  26. Durham SR, Walker SM, Varga E-M, Jacobson MR, O’Brien F, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med. 1999;341:468–475.Cited Here… | PubMed | CrossRef
  27. 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.Cited Here… | PubMed | CrossRef
  28. Tabar AI, Echechipia S, Garcia BE, Olaguibel JM, Lizaso MT, et al. Double-blind comparative study of cluster and conventional immunotherapy schedules and Dermatophagoides pteronyssinus. J Allergy Clin Immunol. 2005;116:109–118.Cited Here… | PubMed | CrossRef
  29. Portnoy J, Bagstad K, Kanarek H, Pacheco F, Hall B, Barnes C. Premedication reduces the incidence of systemic reactions during inhalant rush immunotherapy with mixtures of allergenic extracts. Ann Allergy. 1994;73:409–418.Cited Here… | PubMed
  30. Corrigan CJ, Kettner J, Doemer C, Cromwell O. Efficacy and safety of preseasonally-specific immunotherapy with an aluminum-adsorbed six-grass pollen allergoid. Allergy. 2005;60:801–807.Cited Here… | View Full Text | PubMed | CrossRef
  31. Norman PS, Lichtenstein LM, Marsh DG. Studies on allergoids from naturally occurring allergens. IV. Efficacy and safety of long-term allergoid treatment of ragweed hay fever. J Allergy Clin Immunol. 1981;68:460–470.Cited Here… | PubMed | CrossRef
  32. Casanovas M, Martin R, Jimenez C, Caballero R, Fernández-Caldas E. Safety of immunotherapy with therapeutic vaccines containing depigmented and polymerized allergen extracts. Clin Exp Allergy. 2007;37:434–440.Cited Here… | View Full Text | PubMed | CrossRef
  33. Niederberger V, Horak F, Vrtala S, Spitzauer S, Krauth MT, et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A. 2004;101:14677–14682.Cited Here…
  34. Norman PS, Ohman JL Jr, 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.Cited Here…
  35. Verhoef A, Alexander C, Kay AB, Larche M. T cell epitope immunotherapy induces a CD 4+ T cell population with regulatory activity. PLoS Med. 2005;2:253–261.Cited Here…
  36. Drachenberg KJ, Wheeler AW, Stuebner P, Horak F. A well-tolerated grass pollen-specific allergy vaccine containing a novel adjuvant, monophosphoryl lipid A, reduces allergic symptoms after only four preseasonal injections. Allergy. 2001;56:498–505.Cited Here… | View Full Text | PubMed | CrossRef
  37. 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.Cited Here… | PubMed | CrossRef
  38. Taudorf E, Laursen C, Lanner A, Bjorksten B. Oral immunotherapy in birch pollen hay fever. J Allergy Clin Immunol. 1987;80:153–161.Cited Here… | PubMed | CrossRef
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  40. Passalacqua G, Albano M, Ruffoni S, Pronzato C, Riccio AM, et al. Nasal Immunotherapy to Parietaria: evidence of reduction of local allergic inflammation. Am J Respir Crit Care Med. 1995;152:461–466.Cited Here… | PubMed
  41. Tari MG, Mancino M, Monti G. Immunotherapy by inhalation of allergen in powder in house dust allergic asthma. A double-blind study. J Invest Allergo Clin Immunol. 1992;2:59–67.Cited Here…
  42. Georgitis JW, Nickelsen JA, Wypych JI, Barde SH, Clayton WF, Reisman RE. Local intranasal immunotherapy with high-dose polymerized ragweed extract. Int Archs Allergy Appl Immunol. 1986;81:170–173.Cited Here… | PubMed | CrossRef
  43. Andri L, Senna G, Betteli C, Givanni S, Dimitri G, et al. Local nasal Immunotherapy for Dermatophagoides-induced rhinitis: efficacy of a powder inhaler. J Allergy Clin Immunol. 1993;91:987–996. Cited Here… | PubMed | CrossRef

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