Future forms of immunotherapy
2010; Elsevier BV; Volume: 127; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2010.10.034
ISSN1097-6825
AutoresThomas B. Casale, Jeffrey R. Stokes,
Tópico(s)Food Allergy and Anaphylaxis Research
ResumoAllergic respiratory diseases affect approximately 15% of the US population. Allergen immunotherapy has been a treatment option for diseases such as allergic rhinitis, allergic asthma, and venom allergy for the last 100 years. During the first 75 years, conventional subcutaneous immunotherapy did not change much. However, the last 25 years has seen substantial growth in the development of alternatives to conventional subcutaneous immunotherapy. The addition of omalizumab, an anti-IgE mAb, to immunotherapy offers the potential for increased safety and efficacy. Activation of the innate immune system through Toll-like receptor agonists with and without specific allergens appears to improve the immunologic responses and clinical outcomes in patients with allergic diseases. The use of chemically altered allergens, allergoids, recombinant allergens, and relevant T-cell epitope peptides are all approaches that have yielded positive results. Finally, alternative modes of delivery hold promise, with sublingual immunotherapy rapidly approaching mainstream use in many countries. One thing is clear: the next century of immunotherapy will be vastly different from today's current standard of care. Allergic respiratory diseases affect approximately 15% of the US population. Allergen immunotherapy has been a treatment option for diseases such as allergic rhinitis, allergic asthma, and venom allergy for the last 100 years. During the first 75 years, conventional subcutaneous immunotherapy did not change much. However, the last 25 years has seen substantial growth in the development of alternatives to conventional subcutaneous immunotherapy. The addition of omalizumab, an anti-IgE mAb, to immunotherapy offers the potential for increased safety and efficacy. Activation of the innate immune system through Toll-like receptor agonists with and without specific allergens appears to improve the immunologic responses and clinical outcomes in patients with allergic diseases. The use of chemically altered allergens, allergoids, recombinant allergens, and relevant T-cell epitope peptides are all approaches that have yielded positive results. Finally, alternative modes of delivery hold promise, with sublingual immunotherapy rapidly approaching mainstream use in many countries. One thing is clear: the next century of immunotherapy will be vastly different from today's current standard of care. Information for category 1 CME creditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: January 2011. Credit may be obtained for these courses until December 31, 2012.Copyright Statement: Copyright © 2011-2013. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: Thomas B. Casale, MD, and Jeffrey R. Stokes, MDActivity Objectives1.To identify new forms of allergen immunotherapy.2.To understand the science and technologies behind emerging forms of immunotherapy.3.To understand the safety and efficacy of emerging forms of immunotherapy.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: T. B. Casale is on the Stallergenes advisory board; has received research support from Novartis, Genentech, Stallergenes, and Schering-Plough; and is Executive Vice President of the American Academy of Allergy, Asthma & Immunology. J. R. Stokes has received speaker's honoraria from the Advancing Respiratory Care Network subset of the Respiratory Allergic Disease Foundation and has received research support from Novartis, Genentech, Stallergenes, and Schering-Plough.Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.Allergic diseases have increased in prevalence over the last 20 years, affecting as many as 40 to 50 million persons in the United States. Allergen immunotherapy has been a treatment option for allergic disease since it was first introduced by Noon1Noon L. Prophylactic inoculation against hay fever.Lancet. 1911; 1: 1572Abstract Scopus (1109) Google Scholar and Freeman2Freeman J. Further observations on the treatment of hay fever by hypodermic inoculations of pollen vaccine.Lancet. 1911; 2: 814-817Abstract Scopus (238) Google Scholar nearly a century ago. Allergen immunotherapy alters the course of allergic diseases, thereby reducing symptoms and medication use. A recent meta-analysis of 51 studies with 2871 patients with allergic rhinitis demonstrated a reduction in symptoms by 73% and medication use by 57% with subcutaneous immunotherapy (SCIT).3Calderon M.A. Alves B. Jacobson M. Hurwitz B. Sheikh A. Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis.Cochrane Database Syst Rev. 2007; (CD001936)PubMed Google Scholar In addition to allergic rhinitis, multiple placebo-controlled trials have demonstrated the effectiveness of SCIT in allergic asthma and stinging insect allergy. For venom allergy, successful completion of SCIT can be considered curative. Other benefits of SCIT include the prevention of new sensitizations and the decreased risk of asthma in patients with allergic rhinitis.4Des Roches A. Paradis L. Menardo J.L. Bouges S. Daures J.P. 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: 450-453Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar, 5Möller C. Dreborg S. Ferdousi H.A. Halken S. Høst A. Jacobsen L. et al.Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study).J Allergy Clin Immunol. 2002; 109: 251-256Abstract Full Text Full Text PDF PubMed Scopus (994) Google ScholarThe mechanism of action of allergen immunotherapy involves shifting a patient's immune response to a specific allergen from a predominately allergic T-lymphocyte (TH2) response to a "nonallergic" T-lymphocyte (TH1) response while inducing regulatory T lymphocytes (Fig 1).6James L.K. Durham S.R. Update on mechanisms of allergen injection immunotherapy.Clin Exp Allergy. 2008; 38: 1074-1088Crossref PubMed Scopus (115) Google Scholar Regulatory T cells downregulate allergic immune responses in part through the release of IL-10 and TGF-β. IL-10 causes a shift from allergen-specific IgE to allergen-specific IgG4, whereas TGF-β increases allergen-specific IgA levels. With allergen immunotherapy, the seasonal increase in allergen-specific IgE levels is blunted, whereas protective allergen-specific IgG4 production is increased.Despite the benefits of SCIT, not everyone improves, and patients are at risk of anaphylaxis caused by allergen immunotherapy. Thus there is a need for safer and more effective allergen immunotherapy strategies, especially for patients with asthma. Newer forms of allergen immunotherapy are designed to lessen TH2 responses to allergens and provide a safer alternative to SCIT. This might involve adding therapy to standard SCIT, altering the allergen extract, or changing the mode of delivery of the allergen extract (Fig 2).Fig 2Future potential immunotherapy treatments in clinical development.View Large Image Figure ViewerDownload Hi-res image Download (PPT)SCIT plus omalizumabOne therapeutic option is the addition of the immunomodulating agent omalizumab, an anti-IgE recombinant humanized mAb approved for use in patients with moderate-to-severe perennial allergic asthma, to SCIT. Omalizumab preceding allergen immunotherapy should provide greater safety by reducing serum IgE and FcεR1 receptors on dendritic cells, mast cells, and basophils. In a double-blind, parallel-group, placebo-controlled trial adults with allergic rhinitis were randomized to either 9 weeks of omalizumab or placebo, followed by 1-day rush or placebo ragweed immunotherapy and then 12 weeks of omalizumab or placebo plus ragweed immunotherapy.7Casale T.B. Busse W.W. Kline J.N. Ballas Z.K. Moss M.H. Townley R.G. et al.Immune Tolerance Network Group. Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis.J Allergy Clin Immunol. 2006; 117: 134-140Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar Omalizumab had a protective effect on allergic-type reactions caused by both rush and maintenance immunotherapy. Omalizumab reduced allergic reactions, including anaphylactic reactions, 5-fold and decreased the use of epinephrine and prednisone to treat anaphylaxis. In addition, the omalizumab plus SCIT arm had less allergic rhinitis symptoms than the SCIT-only group. In children with allergic rhinitis, the addition of omalizumab to maintenance SCIT was more effective in reducing allergic rhinitis symptoms than SCIT alone.8Kuehr J. Brauburger J. Zielen S. Schauer U. Kamin W. Von Berg A. et al.Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis.J Allergy Clin Immunol. 2002; 109: 274-280Abstract Full Text Full Text PDF PubMed Scopus (333) Google ScholarPatients with unstable asthma are at a greater risk of systemic, potentially life-threatening reactions to allergen immunotherapy. A multicenter, double-blind, parallel-group study of adult patients with moderate persistent uncontrolled asthma receiving inhaled corticosteroids underwent treatment with either omalizumab or placebo for 12 weeks before a 4-week, 18-injection cluster SCIT regimen, which was followed by 7 weeks of maintenance allergen immunotherapy to perennial allergens.9Massanari M. Nelson H. Casale T. Busse W. Kianifard F. Geba G.P. et al.Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma.J Allergy Clin Immunol. 2010; 125: 383-389Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar Pretreatment with omalizumab significantly reduced total systemic allergic reactions from SCIT, and patients had fewer severe reactions. In addition, a significantly higher proportion of patients receiving omalizumab were able to reach the target maintenance dose of allergen immunotherapy.These data indicate that omalizumab pretreatment of patients undergoing SCIT confers additional safety to SCIT and added efficacy for symptom control. It remains to be determined whether these positive effects persist if the omalizumab is discontinued while the SCIT is continued for 3 to 5 years. Thus far, the studies have been too short term to address this important issue. Also, it is unclear what immunologic mechanisms are responsible for the added efficacy.Toll-like receptorsToll-like receptors (TLRs) are innate immune receptors designed to respond to a variety of pathogens and induce TH1 and regulatory T-cell responses.10Racila D.M. Kline J.N. Perspectives in asthma: molecular use of microbial products in asthma prevention and treatment.J Allergy Clin Immunol. 2005; 116: 1202-1205Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Endotoxins, such as LPSs, are agonists for TLR-4 receptors.11Tulic M.K. Fiset P.O. Manoukian J.J. Frenkiel S. Lavigne F. Eidelman D.H. et al.Role of toll-like receptor 4 in protection by bacterial lipopolysaccharide in the nasal mucosa of atopic children but not adults.Lancet. 2004; 363: 1689-1697Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar TLR9 responds to nucleotide sequences of unmethylated CpGs, which are common in bacterial DNA but are suppressed and methylated in eukaryotic DNA. There have been a variety of strategies using these TLR agonists to improve traditional SCIT.Pollinex Quattro (Allergy Therapeutics, West Sussex, United Kingdom) is a short pollen extract that is chemically modified by glutaraldehyde and adsorbed onto L-tyrosine with the addition of the TLR-4 agonist monophosphoryl lipid A. Therapeutic trials have been conducted in both pediatric and adult patients with allergic rhinitis, allergic conjunctivitis, and asthma to grasses, trees, or ragweed.12Gawchik S.M. Saccar C.L. Pollinex Quattro Tree: allergy vaccine.Expert Opin Biol Ther. 2009; 9: 377-382Crossref PubMed Scopus (21) Google Scholar, 13McCormack P.L. Wagstaff A.J. Ultra-short-course seasonal allergy vaccine (Pollinex Quattro).Drugs. 2006; 66: 931-938Crossref PubMed Scopus (37) Google Scholar Pollinex Quattro is administered as a preseasonal course of 4 injections over at least 3 weeks annually. Therapy has been shown to significantly reduce skin prick test reactions and the seasonal allergen-induced increase in IgE levels while increasing allergen-specific IgG levels.13McCormack P.L. Wagstaff A.J. Ultra-short-course seasonal allergy vaccine (Pollinex Quattro).Drugs. 2006; 66: 931-938Crossref PubMed Scopus (37) Google Scholar In a postmarketing survey of more than 3000 patients given 21,428 injections over 3 years, allergic rhinitis symptoms improved in 93% of patients, and medication use decreased in 75%. Local reactions occurred after 6.3% of injections and systemic reactions occurred after 0.5% (mainly rhinitis symptoms), with no serious or anaphylactic reactions reported.14Zielen S. Metz D. Sommer E. Scherf H.P. Short-term immunotherapy with allergoids and the adjuvant monophosphoryl lipid a. Results from a 3-year post-marketing surveillance study.Allergologie. 2007; 30: S1-S9Google Scholar Similar results were seen in a pediatric population of more than 400 patients, with response to treatment assessed as good or very good in 94% of patients. Rescue medication use decreased from 83% to 24% after the first treatment course and to 13% after the second course.15Rosewich M. Schulze J. Fischer von Weikersthal-Drachenberg K.J. Zielen S. Ultra-short course immunotherapy in children and adolescents during a 3-yrs post-marketing surveillance study.Pediatr Allergy Immunol. 2010; 21: e185-e189Crossref PubMed Scopus (33) Google Scholar Early trials in the United States have demonstrated positive results for both grass and ragweed but have been temporarily suspended because of an adverse event and the ensuing evaluation as to causality.Early studies with inhaled CpG immunostimulatory sequences (ISSs) on allergen-induced airway responses altered the TH1 profile by stimulating expression of IFN-γ and interferon-inducible genes.16Gauvreau G.M. Hessel E.M. Boulet L.P. Coffman R.L. O'Byrne P.M. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses.Am J Respir Crit Care Med. 2006; 174: 15-20Crossref PubMed Scopus (121) Google Scholar However, there was no effect on allergen-induced early or late decreases in FEV1 compared with placebo, nor was there a reduction in allergen-induced sputum eosinophil numbers or TH2-related gene expression.16Gauvreau G.M. Hessel E.M. Boulet L.P. Coffman R.L. O'Byrne P.M. Immunostimulatory sequences regulate interferon-inducible genes but not allergic airway responses.Am J Respir Crit Care Med. 2006; 174: 15-20Crossref PubMed Scopus (121) Google ScholarCovalently bonding an ISS with an allergen, such as ragweed antigen (Amb a 1), dramatically enhanced the ability of ISSs to modify antibody and T-cell responses to the allergen by reducing allergenicity and improving immunogenicity, especially TH1 responses.17Tighe H. Takabayashi K. Schwartz D. Van Nest G. Tuck S. Eiden J.J. et al.Conjugation of immunostimulatory DNA to the short ragweed allergen Amb a 1 enhances its immunogenicity and reduces its allergenicity.J Allergy Clin Immunol. 2000; 106: 124-134Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 18Higgins D. Rodriguez R. Milley R. Marshall J. Abbate C. dela Cruz T. et al.Modulation of immunogenicity and allergenicity by controlling the number of immunostimulatory oligonucleotides linked to Amb a 1.J Allergy Clin Immunol. 2006; 118: 504-510Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar In vitro studies with CpG ISSs in combination with Amb a 1 reversed the ragweed-induced TH2 profile, with decreased IL-5 secretion and increased IFN-γ production from PBMCs.19Marshall J.D. Abtahi S. Eiden J.J. Tuck S. Milley R. Haycock F. et al.Immunostimulatory sequence DNA linked to the Amb a 1 allergen promotes T(H)1 cytokine expression while downregulating T(H)2 cytokine expression in PBMCs from human patients with ragweed allergy.J Allergy Clin Immunol. 2001; 108: 191-197Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar A follow-up in vivo study demonstrated that ragweed-induced TH2 responses were shifted toward TH1 responses, with significant increases in IFN-γ levels.20Simons F.E. Shikishima Y. Van Nest G. Eiden J.J. HayGlass K.T. Selective immune redirection in humans with ragweed allergy by injecting Amb a 1 linked to immunostimulatory DNA.J Allergy Clin Immunol. 2004; 113: 1144-1151Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar In an early clinical study, ragweed-sensitive patients with allergic rhinitis received 6 escalating doses of Amb a 1–immunostimulatory conjugate (AIC; trade name TOLAMBA; Dynavax Technologies, Berkeley, Calif) or placebo before the ragweed season.21Tulic M.K. Fiset P.O. Christodoulopoulos P. Vaillancourt P. Desrosiers M. Lavigne F. et al.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 Patients treated with the conjugate had a significantly reduced increase in eosinophil and IL-4 mRNA–positive cell numbers and an increased number of IFN-γ mRNA–positive cells compared with those seen in placebo-treated patients 4 to 5 months later. No symptom improvement was noted after the initial ragweed season, but during the following ragweed season, AIC-treated patients had less chest symptoms and a trend toward less nasal symptoms.21Tulic M.K. Fiset P.O. Christodoulopoulos P. Vaillancourt P. Desrosiers M. Lavigne F. et al.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 Another phase II study with 6 escalating doses of AIC once weekly before the ragweed season resulted in decreased peak season rhinitis symptoms and medication use during both the first and subsequent ragweed seasons.22Creticos P.S. Schroeder J.T. Hamilton R.G. Balcer-Whaley S.L. Khattignavong A.P. Lindblad R. et al.Immune Tolerance Network GroupImmunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis.N Engl J Med. 2006; 355: 1445-1455Crossref PubMed Scopus (498) Google Scholar The seasonal Amb a 1–specific IgE antibody levels were suppressed for both seasons, whereas a transient Amb a 1–specfic IgG level increase was noted only during the first season. Immediate skin test reactivity was also decreased in the conjugate-treated patients compared with that seen in the placebo-treated patients. In addition, the ragweed-induced TH2 cytokine profile was inhibited, and IFN-γ mRNA levels were increased in nasal mucosa after AIC therapy.23Tulic M.K. Christodoulopoulos P. Fiset P.O. Vaillancourt P. Lavigne F. Marshall J.D. et al.Local induction of a specific Th1 immune response by allergen linked immunostimulatory DNA in the nasal explants of ragweed-allergic subjects.Allergol Int. 2009; 58: 565-572Crossref PubMed Scopus (7) Google ScholarHowever, the development of TOLAMBA was discontinued after interim analysis of 716 patients in a large multisite trial demonstrated only minimal ragweed-induced allergic rhinitis symptoms in the placebo group, and as a result, no meaningful efficacy data could be measured. Patients from the Midwest (more than half the study patients) treated with placebo did have greater ragweed symptoms, and the TOLAMBA-treated patients had reduced total nasal symptom scores.24Dynavax reports interim TOLAMBA ragweed allergy results from DARTT trial. Dynavax Technologies, Berkeley (CA)2007Google Scholar This illustrates the importance of the proper conduct of studies and the selection of appropriate patients to meet key end points.Another therapeutic option involves packaging CpG ISSs into virus-like particles (VLPs) to protect them against proteases, decrease adverse reactions, and improve uptake by antigen-presenting cells. Both subcutaneous and intramuscular administration of house dust mite (HDM) allergen extract plus CpG inserted into VLPs markedly increased HDM-specific IgG and IgM levels within 30 days of treatment.25Kündig T.M. Senti G. Schnetzler G. Wolf C. Prinz Vavricka B.M. Fulurija A. et al.Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults.J Allergy Clin Immunol. 2006; 117: 1470-1476Abstract Full Text Full Text PDF PubMed Scopus (169) Google ScholarA phase I/IIa study evaluated subcutaneous injection of CpG ISSs contained in VLPs (CYT003-QbG10) together with HDM allergen for 10 weeks in 20 patients with HDM allergy.26Senti G. Johansen P. Haug S. Bull C. Gottschaller C. Müller P. et al.Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial.Clin Exp Allergy. 2009; 39: 562-570Crossref PubMed Scopus (183) Google Scholar After treatment with QbG10, skin test reactivity to HDM was reduced, and this effect persisted for up to 38 weeks. The median individual increase in conjunctival allergen provocation dose was 100-fold greater after the treatment, with 1 patient demonstrating a 10,000-fold increase. Within 10 weeks of therapy, patients were nearly symptom free, and the clinical benefit lasted for 38 weeks after treatment. After treatment, allergen-specific IgG levels increased, whereas there was a transient increase in allergen-specific IgE levels. A follow-up randomized, double-blind, placebo-controlled phase II study of patients with mild-to-moderate perennial allergic rhinoconjunctivitis treated weekly for 6 weeks with subcutaneous injections of either CYT003-QbG10 alone (without antigen) or placebo has been completed.27Blaziene A. Leisyte P. Sitkauskiene B. Kits L. Savisaar M. Lozovskis V. et al.CYT003-QbG10, A novel allergen-independent immunotherapy, shown to be safe and efficacious in placebo-controlled phase II study.Ann Allergy Asthma Immunol. 2009; 102: S8Google Scholar CYT003-QbG10 led to improvements in both asthma and rhinitis symptoms. A large phase IIb study with 300 patients with perennial rhinitis is underway. In addition, a press release from Cytos (Zurich, Switzerland) indicated that in a 63-patient study CYT003-QbG10 improved symptoms and pulmonary functions in patients with chronic persistent asthma receiving inhaled corticosteroids.These data suggest that TLR agonists either in combination with allergen or alone might evoke unique immunologic responses that could lead to novel and effective immunotherapy regimens in the future.AllergoidsThe modification of allergens with glutaraldehyde or formaldehyde produces allergoids, which theoretically reduce IgE epitopes while preserving T-cell epitopes.28Henmar H. Lund G. Lund L. Petersen A. Würtzen P.A. Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy.Clin Exp Immunol. 2008; 153: 316-323Crossref PubMed Scopus (44) Google Scholar Allergoids are commonly used in European SCIT, but there are no current US Food and Drug Administration–approved products in the United States. Pollinex Quattro is a unique allergoid because of the addition of the TLR-4 agonist monophosphoryl lipid A. Another compound, Allergovit (Allergopharma KG, Reinbek, Germany), is an aluminum hydroxide–adsorbed depot allergoid preparation of 6 grass pollen allergens. In a 2-year, double-blind, placebo-controlled study in patients with allergic rhinoconjunctivitis, treatment with Allergovit reduced symptom and medication scores, increased grass-specific IgG1 and IgG4 levels, and increased allergen tolerance by means of conjunctival provocation testing.29Corrigan C.J. Kettner J. Doemer C. Cromwell O. Narkus A. Study GroupEfficacy and safety of preseasonal-specific immunotherapy with an aluminium-adsorbed six-grass pollen allergoid.Allergy. 2005; 60: 801-807Crossref PubMed Scopus (166) Google Scholar Improvements in medication and symptom scores and quality of life continued after a third year of treatment.30Williams A. Henzgen M. Rajakulasingam K. Additional benefit of a third year of specific grass pollen allergoid immunotherapy in patients with seasonal allergic rhinitis.Eur Ann Allergy Clin Immunol. 2007; 39: 123-126PubMed Google Scholar In the pediatric population symptomatic and inflammatory parameter improvement have also been demonstrated with Allergovit. These changes include decreases in seasonal grass-specific IgE level increases and inhibition of the production of IL-4. Skin test and nasal reactivity also decreased in the actively treated patients after 1 year of immunotherapy.Depogoid (Leti Pharma GmbH, Witten, Germany), an allergoid to tree pollen, improved combined rhinoconjunctivitis symptom and medication scores compared with placebo, with 64% of patients responding to therapy.31Pfaar O. Robinson D.S. Sager A. Emuzyte R. Immunotherapy with depigmented-polymerized mixed tree pollen extract: a clinical trial and responder analysis.Allergy. 2010; ([Epub ahead of print])PubMed Google Scholar In children with asthma, the use of allergoid SCIT to dust mite improved morning peak flows while reducing the inhaled corticosteroid dose compared with placebo.32Zielen S. Kardos P. Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: a randomized controlled trial.J Allergy Clin Immunol. 2010; ([Epub ahead of print])PubMed Google Scholar One concern is that the low allergenicity of allergoids in comparison with standard extracts might actually be associated with reduced immunogenicity.28Henmar H. Lund G. Lund L. Petersen A. Würtzen P.A. Allergenicity, immunogenicity and dose-relationship of three intact allergen vaccines and four allergoid vaccines for subcutaneous grass pollen immunotherapy.Clin Exp Immunol. 2008; 153: 316-323Crossref PubMed Scopus (44) Google Scholar Nonetheless, this remains a promising alternative approach to traditional SCIT, and future studies should be encouraged.Recombinant allergensRecombinant allergens are purified allergens produced by using the allergen's known molecular, immunologic, and biological characteristics. One form is a recombinant wild-type allergen in which the allergen is produced to mimic the properties of the natural allergen. Recombinant allergens can also be produced to reduce allergenic activity, increase immunogenicity, or both.33Valenta R. Niederberger V. Recombinant allergens for immunotherapy.J Allergy Clin Immunol. 2007; 119: 826-830Abstract Full Text Full Text PDF PubMed Scopus (169) Google ScholarTwo studies in 2005 evaluated the use of recombinant wild-type pollen extracts in patients with allergic rhinitis. The first used a mixture of 5 different recombinant allergens of timothy grass in a randomized, double-blind, placebo-controlled study on 62 patients with allergic rhinitis.34Jutel M. Jaeger L. Suck R. Meyer H. Fiebig H. Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens.J Allergy Clin Immunol. 2005; 116: 608-613Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar Patients were treated with subcutaneous injections for 18 months. Patients receiving recombinant therapy compared with placebo had a 36% decrease in both symptoms and medication use during the grass season. By the first pollen season, some improvement in quality-of-life scores was present in the patients receiving active treatment, and significant improvements in 5 of 7 domains were shown in the second pollen season. Active treatment led to an increase in grass-specific IgG1 levels and a 4000-fold increase in IgG4 levels, with no change in allergen-specific IgE levels. About 1% of recombinant grass allergen injections led to systemic reactions.34Jutel M. Jaeger L. Suck R. Meyer H. Fiebig H. Cromwell O. Allergen-specific immunotherapy with recombinant grass pollen allergens.J Allergy Clin Immunol. 2005; 116: 608-613Abstract Full Text Full Text PDF PubMed Scopus (450) Google ScholarThe second study was a multicenter, randomized, double-blind, placebo-controlled trial comparing recombinant birch pollen allergen vaccine, standard birch pollen extract, natural purified birch pollen allergen, and p
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