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1 KISEP Information Korean J Otolaryngol 2005;48: 이재서 Immunotherapy for Allergic Rhinitis:Current and Future Chae-Seo Rhee, MD Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University College of Medicine, Seoul, Korea 1312

2 이재서 Patient presents with allergic rhinitis for which immunotherapy may be appropriate Evidence of specific IgE antibodies? Test results correlate with clinical symptoms and exposure No Not a condidate for immunotherapy Yes Assess Risks and benefits of appropriate management options Immunotherapy Allergen exposure reduction Medications Patient preferences Response to previous treatment Severity of disease Is immunotherapy recommended for this patient? No Immunotherapy not given Yes Obtain informed consent Counsel and educate patient about the benefits and risks of immunotherapy Identify Specific allergen vaccines Starting dose and immunotherapy schedule Maintenance dose Administer Immunotherapy Safety equipment and procedures in place Twenty-to 30-minute wait in office after injection Consideration of peak flow rate Reaction to Immunotherapy injection? Yes Manage reaction Assess immunotherapy Consider dose or schedule adjustment Consider discontinuing immunotherapy No Assess at follow-up Clinical response to immunotherapy e.g., symptoms, medication use Immunotherapy schedule, reactions, compliance Continuation/discontinuation of immunotherapy treatment Fig. 1. Algorithm for allergen immunotherapy Adapted from Ann Allergy Asthma Immunol 알레르겐의선택 치료스케줄 1313

3 Table 1. Recommended maintenance doses of allergen immunotherapy Allergen Dose, standardized units Dose, major allergen Maintenance concentrate, wt/vol* Dermatophagoides pteronyssinus 600 AU 712 g Der p 1 NA Dermatophagoides farinae 2,000 AU 10 g Der f 1 NA Cat 2,0003,000 BAU 1117 g Fel d 1 NA Grass e.g., timothy 4,000 BAU 7 g Phl p 5 NA Short ragweed standardized NA 624 g Amb a Other pollen nonstandardized NA ND Fungi/mold nonstandardized NA ND Based on a maintenance injection of 0.5 ml. AUallergy unit, BAUbioequivalent allergy unit, NAnot applicable, NDnot determined 1314 Table 2. Sample buildup schedule for weekly immunotherapy Dilution, vol/vol Volume, ml 11, Maintenance concentrate Dilutions are expressed as volume per volume from the maintenance concentrate vaccine. Korean J Otolaryngol 2005;48:

4 이재서 Table 3. Sample schedule for cluster immunotherapy comparing with conventional schedule Week Cluster schedule Conventional schedule Dose BU Total dose BU Total dose g of Der p 1 Dose BU Total dose BU Total dose g of Der p Interval of injection30 minutes. Only placebo doses were administered to the cluster group from weeks 7 to 12. The maintenance immunotherapy doses were administered at weeks 15 and 18 and were continued every 4 weeks up to the end of 1 year. 1315

Antigen Presenting Cell CD4 CD25 IL-10 TGF- IgE IgG4 IgA IT IL-4 Allergic Response IT IL-5 Fig. 2. Summary of the effects of immunotherapy on T-cell responses.

5 Antigen Presenting Cell CD4 CD25 IL-10 TGF- IgE IgG4 IgA IT IL-4 Allergic Response IT IL-5 Fig. 2. Summary of the effects of immunotherapy on T-cell responses. T regt regulatory cell, DC dendritic cell, EOSeosinophil Adapted from J Allergy Clin Immunol IFN- NH2 NH2 Reactive to NH2 Reactive to SH SH FcRI expression and IgE-dependent mast cell activation Eosinophil survival and activation ssmcc CD4 + CD25 + IL-10 A Antigen ISS-ODN IgG4 IgE-dependent antigen presentation IL-10 and cell contact Ag ISSAg C-ODNAg Western Cytokines and proliferation Fig. 3. Summary of the potential antiallergic properties of IL-10 on different limbs of the allergic immune response. EOSeosinophil, T regt regulatory cell Adapted from J Allergy Clin Immunol T-lymphocyte response 1316 B UV shadow Fig. 4. Synthesis of antigen ISS-ODN conjugates AICs. AAICs are synthesized by using sulfosuccinimidyl-4-[n-maleimidomethyl]- cyclohexane-1-carboxylate ssmcc to chemically cross-link NH2 groups on protein antigen with sulfhydryl SH groups on ODNs. BVisualization of antigen Ag, ISS-ODNAg conjugate ISS Ag, and control ODNAg conjugate C-ODNAg by Western blot after sodium dodecyl sulfate polyacrylamide gel electrophoresis shows higher molecular weight bands for the conjugates compared to native protein. The ODNs contained in the conjugates are also visible by ultraviolet UV shadowing of the gel Adapted from Immunol Rev Korean J Otolaryngol 2005;48:

6 이재서 in vitro 항체반응의변화 (Changes in antibody response)

7 SLIT 1318 Korean J Otolaryngol 2005;48:

8 이재서 경구투여면역요법 비내면역요법 저용량면역요법 (low dose immunotherapy) Recombinant peptide 1319

9 - DNA vaccine Adjuvant 항 IgE 항체 CXCR4 AMD3100 T-Lymphocyte Th1 augmentation IFN- IL-12 CpG immunotherapy IL-18 Signaling molecules T-bet GATA-3 STAT-6 Anti-CD11a antibody CD11a Th2 inhibition IL-4 antagonist Anti IL-5 antibody IL-13 Fig. 5. Many immunomodulation targets have some regulatory effect on T-lymphocyte function. Experimental and theoretical targets include augmenting the T helper type 1 response or inhibiting the T helper type 2 response through cytokines, cytokine receptors, chemokine receptors, or signaling molecules. Other targets may include adhesion molecules, such as CD11a, to decrease the extravasation of effector lymphocytes into tissues Adapted from Curr Opin Allergy Clin Immunology Korean J Otolaryngol 2005;48:

10 이재서 T 림프구를목표로하는치료법 - REFERENCES 1) Ray NF, Baraniuk JN, Thamer M, Rinehart CS, Gergen PJ, Kaliner M, et al. Direct expenditures for the treatment of allergic rhinoconjunctivitis in 1996, including the contributations of related airway illness. J Allergy Clin Immunol 1999;103: ) Ross RN. The costs of allergic rhinitis. Am J Manag Care 1996;2: ) Togias A. Rhinitis and asthma: Evidence for respiratory system integration. J Allergy Clin Immunol 2003;111: ) Durham SR, Walker SM, Varga EM, Jacobson MR, O Brien F, Noble W, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341: ) Secrist H, DeKruyff RH, Umetsu DT. Interleukin 4 production by CD4+ T cells from allergic individuals is modulated by antigen concentration and antigen-presenting cell type. J Exp Med 1995;181: ) Reider N, Reider D, Ebner S, Holzmann S, Herold M, Fritsch P, et al. Dendritic cells contribute to the development of atopy by an insufficieny in IL-12 production. J Allergy Clin Immunol 2002;109: ) Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U, Schenk S, 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 Ph1 p 1, a major grass pollen allergen. Clin Exp Allergy 1997;27: ) Secrist H, Chelen CJ, Wen Y, Marshall JD, Umetsu DT. Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J Exp Med 1993;178: ) Till SJ, Francis JN, Nouri-Aria K, Durham SR. Mechanisms of immunotherapy. J Allergy Clin Immunol 2004;113: ) Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in spe-cific immunotherapy. J Clin Invest 1998;102: ) Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol 2003; 111: ) Vissers JL, van Esch BC, Hofman GA, Kapsenberg ML, Weller FR, van Oosterhout AJ. Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model. J Allergy Clin Immunol 2004;113: ) Gehlhar K, Schlaak M, Becker W, Bufe A. Monitoring allergen immunotherapy of pollen-allergic patients: The ratio of allergen-specific IgG4 to IgG1 correlates with clinical outcome. Clin Exp Allergy 1999; 29: ) Lichtenstein LM, Ishizaka K, Norman PS, Sobotka AK, Hill BM. IgE antibody measurements in ragweed hay fever. Relationship to clinical severity and the results of immunotherapy. J Clin Invest 1973;52: ) Malbec O, Fong DC, Turner M, Tybulewicz VL, Cambier JC, Fridman WH, et al. Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation. J Immunol 1998;160: ) Kolbe L, Heusser CH, Kolsch E. Isotype-associated recognition of allergen epitopes and its modulation by antigen dose. Immunology 1995;84: ) Des Roches A, Paradis L, Knani J, Hejjaoui A, Dhivert H, Chanez P, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy 1996;51: ) Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79: ) Wood RA, Phipatanakul W, Hamilton RG, Eggleston PA. A comparison of skin prick tests, intradermal skin tests, and RASTs in the diagnosis of cat allergy. J Allergy Clin Immunol 1999;103: ) Berg TL, Johansson SG. Allergy diagnosis with the radioallergosorbent test: A comparison with the results of skin and provocation tests in an unselected group of children with asthma and hay fever. J 1321

11 Allergy Clin Immunol 1974;54: ) Joint Task Force on Practice Parameters. Allergen immunotherapy: A practice parameter. American academy of allergy, asthma and immunology. American college of allergy, asthma and immunology. Ann Allergy Asthma Immunol 2003;90: ) Rolinck-Werninghaus C, Kopp M, Liebke C, Lange J, Wahn U, Niggemann B. Lack of detectable alterations in immune responses during sublingual immunotherapy in children with seasonal allergic rhinoconjunctivitis to grass pollen. Int Arch Allergy Immunol 2005; 136: ) Fanta C, Bohle B, Hirt W, Siemann U, Horak F, Kraft D, et al. Systemic immunological changes induced by administration of grass pollen allergens via the oral mucosa during sublingual immunotherapy. Int Arch Allergy Immunol 1999;120: ) Marcucci F, Sensi L, Di Cara G, Incorvaia C, Frati F. Dose dependence of immunological response to sublingual immunotherapy. Allergy 2005;60: ) Bagnasco M, Mariani G, Passalacqua G, Motta C, Bartolomei M, Falagiani P, et al. 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J Allergy Clin Immunol 1984;74: ) Andri L, Senna G, Betteli C, Givanni S, Andri G, Falagiani P. Local nasal immunotherapy for Dermatophagoides-induced rhinitis: Efficacy of a powder extract. J Allergy Clin Immunol 1993;91: ) Passalacqua G, Altrainetti V, Mariani G, Falagiani P, Mistrello G, Braizzolara R, et al. Pharmahokinetics of radi-olabelled Par j 1 adminstered intranasally to allergic and healthy subjects. Clin Exp Allergy 2005;35: ) Van Metre TE Jr, Adkinson NF Jr, Lichtenstein LM, Mardiney MR Jr, Norman PS Jr, Rosenberg GL, et al. A controlled study of the effectiveness of the Rinkel method of immunotherapy for ragweed pollen hay fever. J Allergy Clin Immunol 1980;65: ) Müller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, et al. Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. 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Atopy and the human IL-4 receptor alpha chain. J Allergy Clin Immunol 2000;106:S65-S71. 44) Hsu CH, Lin SS, Liu FL, Su WC, Yeh SD. Oral administration of a mite allergen expressed by zucchini yellow mosaic virus in cucurbit species downregulates allergen-induced airway inflammation and IgE synthesis. J Allergy Clin Immunol 2004;113: Korean J Otolaryngol 2005;48:

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy