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• W2036694801 abstract "New knowledge about the pathogenesis of allergic and immunologic diseases has led to a variety of novel targeted therapeutic approaches. Many immunomodulators are currently under development for the therapy of asthma and allergic and immunologic diseases and are undergoing human clinical trials. The study of immunomodulators in human subjects is ultimately required to determine their therapeutic utility because several agents showing promise in in vitro and animal models have failed in human studies. Novel therapeutic approaches include Toll-like receptor 4 and 9 agonists, immunostimulatory oligodeoxynucleotides, oral and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor γ, and nuclear factor κB are also being evaluated for the treatment of allergic diseases, especially asthma. The anti-IgE mAb omalizumab is already used for the treatment of allergic asthma, but its potential role for other allergic diseases has yet to be clearly defined. Overall, the development of new agents that inhibit specific immunopathogenic mechanisms holds promise for beneficial outcomes for patients with the least amount of risk. However,agents that are too specific in their targets might not exhibit therapeutic benefits because of the redundancy of the immune system and the heterogeneity of diseases such as asthma. The goal of this review is to summarize the data from human clinical trials with immunomodulators, discussing the rationale for their use, efficacy results, and putative adverse events associated with them. New knowledge about the pathogenesis of allergic and immunologic diseases has led to a variety of novel targeted therapeutic approaches. Many immunomodulators are currently under development for the therapy of asthma and allergic and immunologic diseases and are undergoing human clinical trials. The study of immunomodulators in human subjects is ultimately required to determine their therapeutic utility because several agents showing promise in in vitro and animal models have failed in human studies. Novel therapeutic approaches include Toll-like receptor 4 and 9 agonists, immunostimulatory oligodeoxynucleotides, oral and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor γ, and nuclear factor κB are also being evaluated for the treatment of allergic diseases, especially asthma. The anti-IgE mAb omalizumab is already used for the treatment of allergic asthma, but its potential role for other allergic diseases has yet to be clearly defined. Overall, the development of new agents that inhibit specific immunopathogenic mechanisms holds promise for beneficial outcomes for patients with the least amount of risk. However,agents that are too specific in their targets might not exhibit therapeutic benefits because of the redundancy of the immune system and the heterogeneity of diseases such as asthma. The goal of this review is to summarize the data from human clinical trials with immunomodulators, discussing the rationale for their use, efficacy results, and putative adverse events associated with them. 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: February 2008. Credit may be obtained for these courses until January 31, 2010.Copyright Statement: Copyright © 2008-2010. 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: Authors: Thomas B. Casale, MD, and Jeffrey R. Stokes, MDActivity Objectives1. To understand the role of immunomodulators in treating allergic diseases and their mechanisms of action.2. To understand the efficacy of immunomodulators in allergic disease based on human clinical trials.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: Thomas B. Casale has consulting arrangements with Genentech, Novartis, OSI, Pharma, and Zymo/Genetics; has received research support from Dynavax, Novartis, Genentech, Amgen, and Schering; and is on the speakers' bureau for Merck, Genentech, and Novartis. Jeffrey R. Stokes is on the speakers' bureau for GlaxoSmithKline.New knowledge about the pathogenesis of allergic and immunologic diseases, including the molecular mechanisms involved, has led to a variety of novel therapeutic approaches. This article reviews some of these new potential treatment modalities that are in human clinical trials. The importance of focusing on human clinical trials has become evident by the failure of treatments that have shown promise in animal models. Novel therapeutic approaches reviewed in this article include Toll-like receptor (TLR) agonists, oral and parenterally administered cytokine blockers, specific cytokine receptor antagonists, transcription factor modulators, and anti-IgE mAbs (Fig 1). The risk/benefit ratio of approaches aimed at certain immunologic processes will also be reviewed. Ultimately, the goal for the therapy of allergic and immunologic diseases should be the induction of immune tolerance, a change in the immune response such that discontinuation of the therapy results in continued long-lasting therapeutic benefits without adverse consequences. The discussion of the economics involved in using some of these agents, especially mAbs, is not included. However, costs should be kept in mind because pharmacoeconomic data need to support the use of expensive medications, especially for disorders that are very common and have little or no mortality. Overall, the development of new agents that specifically inhibit key immunopathogenic mechanisms holds promise for beneficial outcomes for patients.TLRsTLRs play a key role in activating antigen-presenting cells for both innate and adaptive immune responses. Blocking or stimulating TLRs can modify the TH1/TH2 cytokine balance affecting allergic diseases. Eleven different TLRs have been identified. Agonists for TLR4 and TLR9 have been developed and used in clinical trials for the therapy of allergic respiratory diseases. TLR4 binds LPSs and endotoxins expressed on the cell surface. TLR9 binds CpG motifs most common in bacterial pathogens.1Krieg A.M. Therapeutic potential of Toll-like receptor 9 activation.Nat Rev Drug Discov. 2006; 5: 471-484Crossref PubMed Scopus (1037) Google ScholarTLR4 agonistLipid A, the active component of LPS, is a TLR4 agonist that induces TH1 responses. An aqueous formulation of monophosphoryl lipid A, CRX-675, is a TLR4 agonist that has been evaluated as a potential therapy for seasonal allergic rhinitis.2Casale T.B. Kessler J. Romero F.A. Safety of the intranasal toll-like receptor 4 agonist CRX-675 in allergic rhinitis.Ann Allergy Asthma Immunol. 2006; 97: 454-456Abstract Full Text PDF PubMed Scopus (34) Google Scholar Patients were treated with either placebo (n = 16) or CRX-675 (2, 20, 100, or 200 μg administered intranasally; n = 12 per arm) 24 hours before a ragweed intranasal challenge. The adverse event profile of CRX-675–treated patients was similar to that of placebo-treated patients, and no dose-related toxic effects were observed. There was no clear trend in the ability of CRX-675 to inhibit nasal allergen challenge responses, but improvement in nasal symptom scores was observed at 100 μg. Appropriate dosing and timing will ultimately define the potential therapeutic role of CRX-675 or other TLR4 agonists for allergies.TLR9 agonists (immunostimulatory oligonucleotides)Bacterial and viral genomes have immunostimulatory DNA sequences containing unmethylated CpG sequences that are suppressed and methylated in vertebrate genomes. TLR9 is the receptor for CpG DNA, which in human subjects is expressed in highest concentrations on B cells and plasmacytoid dendritic cells. TLR9-activated plasmacytoid dendritic cells produce IFN-α, leading to secondary activation of natural killer T cells, monocytes, and neutrophils. B cells activated by TLR9 produce IL-6 and IL-10 while inducing B-cell differentiation into plasma cells and triggering IgG isotype switching and antibody production.1Krieg A.M. Therapeutic potential of Toll-like receptor 9 activation.Nat Rev Drug Discov. 2006; 5: 471-484Crossref PubMed Scopus (1037) Google Scholar TLR9 agonists activate both the innate and humoral immune system through these interactions.There are 3 classes of CpG molecules, A, B, and C, which are described in Table I. Both B- and C-class CpG oligodeoxynucleotides have been used in vaccine therapy for infectious diseases, cancer, or both.1Krieg A.M. Therapeutic potential of Toll-like receptor 9 activation.Nat Rev Drug Discov. 2006; 5: 471-484Crossref PubMed Scopus (1037) Google Scholar, 3Bhattacharjee R.N. Akira S. Modifying toll-like receptor 9 signaling for therapeutic use.Mini Rev Med Chem. 2006; 6: 287-291Crossref PubMed Scopus (24) Google ScholarTable IThree major classes of CpG oligodeoxynucleotideA class: Chimeric backbone Examples: ODN 2216, 1583 (5′-G∗G∗G-T-C-A-A-C-G-T-T-G-A-G∗G∗G∗G∗G∗G-3′) Responses: High IFN-α, IFN-γ, TH1 inducer, poor B-cell stimulator Target cells: pDC, PBMC, NKB class: Phosphorothioate backbone, linear Examples: ODN PF-3512676, 1018, 1826 (5′-T∗C∗C∗A∗T∗G∗A∗C∗G∗T∗T∗C∗C∗T∗G∗A∗C∗G∗T∗T-3′) Responses: B-cell proliferation, pDC maturation, secrete IgG, high IgM, IP-10, IL-6 Target cells: pDC, monocyte, NK Clinical use: Monotherapy, vaccines, in combination for allergies, CA, infectious diseasesC class: Phosphorothioate backbone, 3′ palindrome, can form duplexes Examples: ODN CPG10101, 5393, 2395 (5′-T∗C∗GT∗C∗G∗T∗T∗T∗T∗C∗G∗G∗C∗G∗C∗G∗C∗G∗C∗C∗G) Responses: Combined intermediate effects of A and B classes, high IFN-α, B-cell activation, strong TH1 inducer Target cells: B cell, pDC, NK cell, PBMC Clinical use: Monotherapy for infectious diseases (hepatitis B)pDC, Plasmacytoid dendritic cell; NK, natural killer; ODN, oligodeoxynucleotide; CA, cancer. Open table in a new tab Murine models of allergic lung disease have demonstrated the effectiveness of CpG in the prevention and reduction of airway inflammation.1Krieg A.M. Therapeutic potential of Toll-like receptor 9 activation.Nat Rev Drug Discov. 2006; 5: 471-484Crossref PubMed Scopus (1037) Google Scholar, 3Bhattacharjee R.N. Akira S. Modifying toll-like receptor 9 signaling for therapeutic use.Mini Rev Med Chem. 2006; 6: 287-291Crossref PubMed Scopus (24) Google Scholar, 4Hayashi R. Raz E. TLR9-based immunotherapy for allergic disease.Am J Med. 2006; 119 (e1-e6): 897Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 5Kline J.N. Eat dirt CpG DNA and immunomodulation of asthma.Proc Am Thorac Soc. 2007; 4: 283-288Crossref PubMed Scopus (51) Google Scholar Conjugation of antigens or allergens to CpG can dramatically improve the efficacy of CpG motifs. Conjugation of Amb a 1 (the predominant ragweed allergen) to CpG induced Amb a 1–specific TH1 immune responses and suppressed TH2 responses in human subjects with ragweed allergy.6Marshall J.D. Abtahi S. Eiden J.J. Tuck S. Milley R. Haycock F. et al.Immunostimulatory sequence DNA linked to Amb a 1 allergen promotes TH1 cytokine expression while downregulating TH2 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 This response was associated with significant increases in IFN-α, CXCL9, and CXCL10 levels and decreases in IL-5, CCL17, and CCL22 levels.7Simons F.E.R. Shiykishima 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 The number of immunostimulatory DNA sequences containing CpG motifs bound to the Amb a 1 protein alters the immunogenicity and allergenicity of the response.8Higgins D. Rodriquez R. Milley R. Marshall J. Abbate C. Cruz T.D. 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 ScholarTolamba is an immunostimulatory oligonucleotide covalently linked to Amb a 1. In a ragweed seasonal allergic rhinitis trial, adult subjects with ragweed allergy were treated with 6 weekly injections of either Tolamba or placebo before the ragweed season and followed for 2 ragweed seasons.9Creticos P.S. Shroeder J.T. Hamilton R.G. Balcer-Whaley S.L. Khattignavong A.P. Lindblad R. et al.Immunotherapy with ragweed-toll-like receptor agonist vaccine for allergic rhinitis.N Engl J Med. 2006; 355: 1445-1455Crossref PubMed Scopus (499) Google Scholar Patients treated with Tolamba experienced a significant reduction in total nasal symptom scores from baseline during the 2-week peak pollen season compared with placebo-treated patients in both the first and second years of the ragweed season. The seasonal increase in Amb a 1–specific IgE levels was suppressed by Tolamba therapy in both years, whereas a transient increase in Amb a 1–specific IgG levels was noted in the first ragweed season. A second study found that nasal biopsy specimens from Tolamba-treated patients had a significantly reduced increase in eosinophils and IL-4 mRNA–positive cells and increased IFN-α mRNA–positive cells compared with those in placebo-treated patients after the ragweed season.10Tulic 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 A large, multicenter, placebo-controlled trial of Tolamba for ragweed-induced seasonal allergic rhinitis showed no clinical benefit. However, the symptom scores were low, even in the placebo group, potentially making it difficult to discern a treatment effect.11Bernstein D.I. Segall N. Nayak A. Casale T. Korenblatt P. Martins E. Safety and efficacy of the novel vaccine Tolamba in ragweed allergic adults, a dose finding study.J Allergy Clin Immunol. 2007; 119: S78-S79Abstract Full Text Full Text PDF Google Scholar Treatment with Tolamba is generally well tolerated.Atopic asthmatic patients were treated with a CpG preparation through inhalation. Despite an increase in IFN-α gene expression, no effect was noted on allergen-induced eosinophils or TH2-related gene expression.12Guavreau 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 Furthermore, no inhibition of airway responses was noted.The application of TLR9 ligands is not limited to allergic disease. Human trials have demonstrated the effectiveness of CpG as either monotherapy or an adjunctive treatment in vaccines in a number of infectious diseases, such as hepatitis B, hepatitis C, anthrax, and influenza.13Krieg A.M. Antiinfective applications of toll-like receptor 9 agonists.Proc Am Thorac Soc. 2007; 4: 289-294Crossref PubMed Scopus (90) Google Scholar CpG is currently being studied in phase II and phase III human trials for cancer treatment, either alone or in combination with standard chemotherapy.14Krieg A.M. Development of TLR9 agonists for cancer therapy.J Clin Invest. 2007; 117: 1184-1194Crossref PubMed Scopus (344) Google ScholarOverall, the data suggest that TLR9 agonists could be valuable as adjuvants for the therapy of a variety of diseases, including allergic respiratory disorders. Indeed, the combination of CpG and allergens might prove more effective, with a better safety profile than allergen immunotherapy alone.Cytokine blockersTherapeutic agents targeting TLRs affect both the innate and humoral arms of the immune system through a multiplicity of action. However, with the potential broad-ranging effects of some agents on the immune system, there is a concern of a shift in the risk/benefit ratio. In contrast, strategies aimed at single or multiple related cytokines might provide a lower risk for adverse events. This must be balanced by the potential of a less-efficacious or nonefficacious therapy. As reviewed below, there are several examples of agents targeting a single cytokine not being effective, perhaps because of the redundancy of the immune system. Anticytokine therapies provide a way to discern the importance of individual molecules in the pathogenesis of human disease.Because TH2 responses are the drivers of allergic responses, agents aimed at blocking key TH2 cytokines have been logical targets for the therapy of allergic diseases. Strategies aimed at blocking the effects of IL-4, IL-5, and IL-13 have been evaluated in several phase I and phase II trials.Oral synthesis inhibitorsTwo oral agents that inhibit cytokine synthesis are undergoing clinical trials. Suplatast tosilate has been shown to inhibit the production of IL-4 and IL-5. Clinical trials with suplatast have shown an improvement in airway inflammation, airway hyperresponsiveness, clinical symptoms, and peak expiratory flow rates. Suplatast has also been shown to decrease serum IgE levels.15Tamaoki J. Kondo M. Sakai N. Aoshiba K. Tagaya E. Nakata J. et al.Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study.Lancet. 2000; 356: 273-278Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 16Horiguchi T. Tachikawa S. Handa M. Hanazono K. Kondo R. Ishibashi A. et al.Effects of suplatast tosilate on airway inflammation and airway hyperresponsiveness.J Asthma. 2001; 38: 331-336Crossref PubMed Scopus (21) Google Scholar, 17Yoshida M. Aizawa H. Inoue H. Matsumoto K. Koto H. Komori M. et al.Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients.J Asthma. 2002; 39: 545-552Crossref PubMed Scopus (21) Google Scholar AVP-13358 has been shown to suppress IgE, CD23, and TH2 cytokine responses ex vivo and in vitro in mouse and human cell assays.18Richards M.L. Lio S.C. Sinha A. Tieu K.K. Sircar J.C. Novel 2-(substituted phenyl) benzimidazole derivatives with potent activity against IgE, cytokines, and CD23 for the treatment of allergy and asthma.J Med Chem. 2004; 47: 6451-6454Crossref PubMed Scopus (45) Google Scholar Avanir Pharmaceuticals has put a hold on clinical trials with this compound, but safety data were favorable.Soluble receptor/mAb therapyAnti–IL-4 strategiesIL-4 induces IgE isotype switching and promotes naive lymphocytes to differentiate into TH2 cells with subsequent release of additional IL-4, IL-5, and IL-13. Two human studies evaluated the efficacy and safety of a recombinant human sIL-4R. sIL-4R was safe and well tolerated, with the serum half-life of an inhaled dose being 5 days. The first study enrolled adult atopic patients with moderate persistent asthma requiring daily inhaled corticosteroids.19Borish L.C. Nelson H.S. Lanz M.J. Claussen L. Whitmore J.B. Agosti J.M. et al.Interleukin-4 Receptor in Moderate Atopic Asthma: a phase I/II randomized, placebo-controlled trial.Am J Respir Crit Car Med. 1999; 160: 1816-1823Crossref PubMed Scopus (431) Google Scholar Patients were dosed one time with nebulized sIL-4R of either 500 μg or 1500 μg or placebo. All inhaled corticosteroids were stopped 1 day prior. Only the patients receiving the 1500-μg dose of sIL-4R had significant improvement in asthma symptom scores, rescue β-agonist use, and exhaled nitric oxide levels compared with those receiving the placebo. The 1500-μg dose also resulted in a significant increase in FEV1 at 4 days. A follow-up study with 62 asthmatic subjects requiring inhaled corticosteroids evaluated weekly dosing of sIL-4R for 12 weeks at 0.75 mg, 1.5 mg, or 3.0 mg and placebo.20Borish L.C. Nelson H.S. Corren J. Bensch G. Busse W.W. Whitmore J.B. et al.Efficacy of soluble IL-4 receptor for the treatment of adults with asthma.J Allergy Clin Immunol. 2001; 107: 963-970Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar Inhaled corticosteroids were discontinued at the start of the study. Only patients receiving 3.0 mg of soluble IL-4 receptor (sIL-4R) weekly through a nebulizer were able to maintain their lung functions. No significant improvements were noted in symptoms or asthma exacerbations. Similarly, an mAb against IL-4 had no proved efficacy, leading to the discontinuation of further exploration into anti-IL-4–specific therapies. This might in part be due to the redundancy in mechanisms between IL-4 and other cytokines, especially IL-13.Anti–IL-5 mAbsIL-5 is required for eosinophil differentiation and survival. Two humanized IL-5 mAbs have been studied in human subjects: reslizumab (SCH55700) and mepolizumab. A small study evaluated subjects with severe persistent asthma treated with one dose of reslizumab (0.03 mg/kg, 0.3 mg/kg, or 1.0 mg/kg) or placebo for 90 days.21Kips J.C. O'Connor B.J. Langley S.J. Woodcock A. Kerstjens H.A.M. Postma D.S. et al.Effect of SCH55700, a humanized anti-human interleukin-5 antibody, in severe persistent asthma: a pilot study.Am J Respir Crit Care Med. 2003; 167: 1655-1659Crossref PubMed Scopus (472) Google Scholar A decrease in serum eosinophils was noted only in the high-dose (1.0 mg/kg) group 30 days after treatment. No significant sustained changes in FEV1, asthma symptom scores, sputum eosinophils, or physician-evaluated overall condition were noted with any dose of reslizumab compared with placebo.Mepolizumab suppressed serum eosinophils in asthmatic subjects without altering T-cell functions.22Büttner C. Lun A. Splettstoesser T. Kunkel G. Renz H. Monoclonal anti-interleukin-5 treatment suppresses eosinophil but not T-cell function.Eur Respir J. 2003; 21: 799-803Crossref PubMed Scopus (109) Google Scholar Studies in patients with mild atopic asthma noted that mepolizumab reduced extracellular matrix protein remodeling and airway eosinphils.23Flood-Page P. Menzies-Gow A. Phipps S. Ying S. Wangoo A. Ludwig M.S. et al.Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics.J Clin Invest. 2003; 112: 1029-1036Crossref PubMed Scopus (710) Google Scholar, 24Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.Am J Respir Crit Care Med. 2003; 167: 199-204Crossref PubMed Scopus (736) Google Scholar Treatment with mepolizumab decreased median serum eosinophils from baseline by 100%, whereas airway eosinophils only decreased by 55%, with decreases in serum eosinophils lasting up to 16 weeks and decreases in sputum eosinophils lasting for 4 weeks.24Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.Am J Respir Crit Care Med. 2003; 167: 199-204Crossref PubMed Scopus (736) Google Scholar, 25Leckie M.J. Brinke A.T. Khan J. Diamant Z. O'Connor B.J. Walls C.M. et al.Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response.Lancet. 2000; 356: 2144-2148Abstract Full Text Full Text PDF PubMed Scopus (1640) Google Scholar However, no effects on clinical measures of asthma, including airway hyperresponsiveness, FEV1, and peak flow measures, were noted.24Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.Am J Respir Crit Care Med. 2003; 167: 199-204Crossref PubMed Scopus (736) Google Scholar, 25Leckie M.J. Brinke A.T. Khan J. Diamant Z. O'Connor B.J. Walls C.M. et al.Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness, and the late asthmatic response.Lancet. 2000; 356: 2144-2148Abstract Full Text Full Text PDF PubMed Scopus (1640) Google ScholarIn patients with atopic dermatitis, mepolizuamb was ineffective in improving physician-based global assessment and pruritis scoring.26Oldhoff J.M. Darsow U. Werfel T. Katzer K. Wulf A. Laifaoui J. et al.Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis.Allergy. 2005; 60: 693-696Crossref PubMed Scopus (264) Google ScholarNasal polyps are frequently associated with increased levels of IL-5. One dose of reslizumab (either 1 or 3 mg/kg) was compared with placebo in the treatment of severe nasal polyposis.27Gevaert P. Lang-Loidolt D. Lackner A. Stammberger H. Staudinger H. Van Zele T. et al.Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps.J Allergy Clin Immunol. 2006; 118: 1133-1141Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar Only 50% of patients treated with reslizumab had improvement in their nasal polyps. The only marker to predict responsiveness to therapy was an increased level of nasal IL-5 (>40 pg/mL) at baseline.Hypereosinophilic syndrome might be a disease more responsive to anti–IL-5. In a small study of patients with hypereosinophilic syndrome, one dose of 1.0 mg/kg reslizumab decreased eosinophil counts to the normal range, with marked improvement of clinical signs and symptoms in 2 of the 4 patients treated.28Klion A.D. Law M.A. Noel P. Kim Y.J. Haverty T.P. Nutman T.B. Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome.Blood. 2004; 103: 2939-2941Crossref PubMed Scopus (148) Google Scholar Eosinophils remained suppressed up to 12 weeks, but as eosinophilia returned, so did the signs and symptoms of hypereosinophilic syndrome. When the 2 responsive patients received further doses, the magnitude and duration of the improvement lessened with each subsequent dose. Mepolizumab has also been evaluated in 2 small studies for hypereosinophilic syndrome.29Plötz S.G. Simon H.U. Darsow U. Simon D. Vassina E. Yousefi S. et al.Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis.N Engl J Med. 2003; 349: 2334-2339Crossref PubMed Scopus (239) Google Scholar, 30Garrett J.K. Jameson S.C. Thomson B. Collins M.H. Wagoner L.E. Freese D.K. et al.Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.J Allergy Clin Immunol. 2004; 113: 115-119Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar Treatment with mepolizumab decreased serum eosinophils to normal levels within 24 hours of administration, with marked symptomatic improvement. Two of the three patients treated remained asymptomatic after cessation of mepolizumab therapy.29Plötz S.G. Simon H.U. Darsow U. Simon D. Vassina E. Yousefi S. et al.Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis.N Engl J Med. 2003; 349: 2334-2339Crossref PubMed Scopus (239) Google Scholar Mepolizumab treatment might have a corticosteroid-sparing effect in patients with hypereosinophilic syndrome.30Garrett J.K. Jameson S.C. Thomson B. Collins M.H. Wagoner L.E. Freese D.K. et al.Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes.J Allergy Clin Immunol. 2004; 113: 115-119Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar Overall, there are too few patients treated to determine whether anti–IL-5 mAb therapy will be a good treatment option, but further studies are warranted.Eosinophilic esophagitis is a chronic eosinophil-associated gastrointestinal disorder defined by high numbers of eosinophils in the esophagus (>20-24 eosinophils per high-power field [hpf]). In a study of 4 patients with dysphagia and eosinophilic strictures, mepolizumab decreased mean esophageal eosinophilia from 46/hpf to 6/hpf and maximal esophageal eosinophil levels from 153/hpf to 28/hpf. In addition, patients had improved quality of life and clinical outcomes.31Stein M.L. Collins M.H. Villanueva J.M. Kushner J.P. Putnam P.E. Buckmeier B.K. et al.Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.J Allergy Clin Immunol. 2006; 118: 1312-1319Abstract Full Text Full Text PDF PubMed Scopus (359) Google ScholarIt is unclear whether monoclonal anti–IL-5 therapy for asthma or atopic dermatitis will be a good therapeutic option. This is likely due to the contribution of noneosino" @default.
• W2036694801 created "2016-06-24" @default.
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• W2036694801 date "2008-02-01" @default.
• W2036694801 modified "2023-09-27" @default.
• W2036694801 title "Immunomodulators for allergic respiratory disorders" @default.
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