Specific immunotherapy (SIT) is the practice of administering increasing doses of allergen extracts to selected subjects suffering from IgE–mediated hypersensitivity, with the ultimate aim of ameliorating the symptoms associated with exposure to the causative allergen. The process is often called hyposensitization or desensitization because one consequence of the treatment is a reduction in sensitivity of the target organ after challenge with the relevant allergen. SIT has been practiced as treatment of type I allergy caused by inhalant allergens and Hymenoptera venoms for more than 80 years on an empirical basis. Today, numerous double–blind, placebo–controlled studies prove the therapeutic effect of SIT. However, the immunological mechanisms underlying successful specific immunotherapy have still not been completely elucidated. This review focuses on recent attempts to characterize the immunological events associated with SIT.

1.
Varney VA, Gaga M, Frew AJ, Aber VR, Kay AB, Durham SR: Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs. BMJ 1991; 302:265–269.
2.
Ortolani C, Pastorello E, Moss RB, Hsu YP, Restuccia M, Joppolo G, Miadonna A, Cornelli U, Halpern G, Zanussi C: Grass pollen immunotherapy: A single year double–blind, placebo–controlled study in patients with grass pollen–induced asthma and rhinitis. J Allergy Clin Immunol 1984;73:283–290.
3.
Bousquet J, Hejjaoui A, Skassa–Brociek W, Guerin B, Maasch HJ, Dhivert H, Michel FB: Double–blind, placebo–controlled immunotherapy with mixed grass pollen allergoids. I. Rush immunotherapy with allergoids and standardized grass pollen extract. J Allergy Clin Immunol 1987;80:591–598.
4.
Norman PS, Winkelwerder W, Lichtenstein L: Immunotherapy of hay fever with ragweed antigen E: Comparisons with whole pollen extract and placebos. J Allergy 1968;42:93–108.
5.
D’Amato G, Kordash TR, Liccardi G, Lobefalo G, Cazzola M, Freshwater LL: Immunotherapy with Alpare in patients with respiratory allergy to Parietaria pollen: A two–year double– blind, placebo–controlled study. Clin Exp Allergy 1995;25:149–158.
6.
Bousquet J, Michel FB: Specific immunotherapy in asthma: Is it effective? J Allergy Clin Immunol 1994;94:1–11.
7.
Warner JO, Price JF, Soothill JF, Hey EN: Controlled trial of hyposensitization to Dermatophagoides pteronyssinus in children with asthma. Lancet 1978;ii:912–915.
8.
Wahn U, Schweter C, Lind P, Lowenstein H: Prospective study on immunologic changes induced by two different Dermatophagoides pteronyssinus extracts prepared from whole mite cultures and mite bodies. J Allergy Clin Immunol 1988;82:360–370.
9.
Van Bever HP, Stevens WJ: Effect of hyposensitization upon the immediate and late asthmatic reaction and upon histamine reactivity in patients allergic to house dust mit (Dermatophagoides pteronyssinus). Eur Respir J 1992; 5:318–322.
10.
Pichler CE, Maquardsen A, Sparholt S, Lowenstein H, Bircher A, Bischof M, Pichler WJ: Specific immunotherapy with Dermatophagoides pteronyssinus and D. farinae results in decreased bronchial hyperreactivity. Allergy 1997;52:274–283.
11.
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.
12.
Müller U, Helbling A, Berchtold E: Immunotherapy with honey–bee venom and yellow jacket venom is different regarding efficacy and safety. J Allergy Clin Immunol 1992;89:529–535.
13.
Des Roches A, Paradis L, Ménerado J–L, Bouges S, Daures 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.
14.
Jacobsen L, Dreborg S, Moller C, Valovirta E, Wahn U, Niggemann B, Koller D, Urbanek R, Halken S, Host A, Lowenstein H: Immunotherapy as a preventive allergy treatment (abstract). J Allergy Clin Immunol 1996;97:232.
15.
Bousquet J, Lockey RF, Malling HJ: WHO Position Paper. Allergen immunotherapy: Therapeutic vaccines for allergic diseases. Allergy 1998;53(suppl):1–42.
16.
Mosbech H, Dreborg S, Madsen F, Ohlsson H, Stahl–Skov P, Taudorf E, Weeke B: High dose grass pollen tablets used for hyposensitization in hay fever patients. A one–year double–blind placebo–controlled study. Allergy 1987;42: 451–455.
17.
Sabbah A, Hassoun S, Le Sellin J, André C, Sicard H: A double–blind, placebo–controlled trial by the sublingual route of immunotherapy with a standardized grass pollen extract. Allergy 1994;49:309–313.
18.
Andri L, Senna G, Andri G, Dama A, Givanni S, Betteli C, Dimitri G, Falagiani P, Mezzelani P: Local nasal immunotherapy for birch allergic rhinitis with extract in powder form. Clin Exp Allergy 1995;97:1092–1099.
19.
Welsh PW, Butterfield JH, Yunginger JW, Agarwal MW, Gleich GJ: Allergen–controlled study of intranasal immunotherapy for ragweed hay fever. J Allergy Clin Immunol 1983;71:454–460.
20.
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;70:261–271.
21.
Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U, Schenk S, Klotz F, Ebner H, Kraft D, Scheiner O: 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: 1007–1015.
22.
Djurup R, Osterballe O: IgG subclass antibody response in grass pollen–allergic individuals undergoing specific immunotherapy. Prognostic value of serum subclass antibody levels early in immunotherapy. Allergy 1984;39:433– 441.
23.
Lichtenstein LM, Holtzman NA, Burnett LS: A quantitative in vitro study of the chromatographic distribution and immunoglobulin characteristics of human blocking antibody. J Immunol 1968;101:317–324.
24.
Hussain R, Poindexter RW, Ottesen EA: Control of allergic reactivity in human filariasis. Predominant localization of blocking antibodies to the IgG–4 subclass. J Immunol 1992;148: 2731–2739.
25.
Birkner T, Rumpold H, Jarolim E, Ebner H, Breitenbach M, Svaril F, Scheiner O, Kraft D: Evaluation of immunotherapy–induced changes in specific IgE, IgG, and IgG–subclasses in birch pollen allergic patients by means of immunoblotting. Allergy 1989;45:418–425.
26.
Jarolim E, Poulsen LK, Stadler BM, Mosbech H, Oesterballe O, Kraft D, Weeke B: A long term follow–up study of hyposensitization with immunoblotting. J Allergy Clin Immunol 1990;85:996–1004.
27.
Van der Zwan JC, Flintermann J, Jankowsky IG, Kerckhaert JA: Hyposensitization to wasp venom in six hours. BMJ 1983;287:1329– 1331.
28.
Birnbaum J, Charpin D, Vervloet D: Rapid Hymenoptera venom immunotherapy: Comparative safety of three protocols. Clin Exp Allergy 1993;23:226–230.
29.
Wierenga AE, Snoek M, DeGroot C, Chrétien I, Bos JD, Jansen HM, Kapsenberg ML: Evidence for compartmentalization of functional subsets of CD4+ T lymphocytes in atopic patients. J Immunol 1990;144:4651–4656.
30.
Romagnani S: Lymphokine production by human T cells in disease states. Annu Rev Immunol 1994;12:227–257.
31.
VanNeerven RJJ, Ebner C, Yssel H, Kapsenberg ML, Lamb JR: T cell responses to allergens: Epitope specificity and clinical relevance. Immunol Today 1996;17:526–532.
32.
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; 178:2123–2130.
33.
Jutel M, Pichler WJ, Skrbic D, Urwyler A, Dahinden C, Müller UR: Bee venom immunotherapy results in decrease of IL–4 and IL–5 and increase of IFN–γ secretion in specific allergen–stimulated T cell cultures. J Immunol 1995;154:4187–4194.
34.
McHugh SM, Deighton J, Steward AG, Lachmann PJ, Ewan PW: Bee venom immunotherapy induces a shift in cytokine responses from a Th2 to a Th1 dominant pattern: Comparison of rush and conventional immunotherapy. Clin Exp Allergy 1995;25:828–838.
35.
Akdis CA, Akdis M, Blesken T, Wymann D, Alkan SS, Müller U, Blaser K: Epitope–specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL–2 and IL–15 in vitro. J Clin Invest 1996;98: 1676–1683.
36.
Varney VA, Hamid QA, Sun Y, 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 response. J Clin Invest 1993;92:644–651.
37.
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–γ. J Allergy Clin Immunol 1996;97:1356–1365.
38.
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.
39.
Carballido JM, Carballido–Perrig N, Terres G, Heusser CH, Blaser K: Bee venom phospholipase A2–specific T cell clones from human allergic and non–allergic individuals: Cytokine patterns change in response to the antigen concentration. Eur J Immunol 1992;22:1357– 1363.
40.
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;181:1081–1089.
41.
Manetti R, Gerosa F, Guidizi MG, Biagiotti MG, Parronchi P, Piccini MP, Sampognaro S, Maggi E, Romagnani S, Trinchieri G: Interleukin–12 induces stable priming for interferon–γ (IFN–γ) production during differentiation of human T helper cells and transient IFN–γ production in established Th2 cell clones. J Exp Med 1994;179:1273–1280.
42.
Constant S, Pfeiffer C, Woodard A, Pasqualini T, Bottomly K: Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ cells. J Exp Med 1995;182: 1591–1596.
43.
Hsieh KH: Changes of lymphoproliferative responses of T cell subsets to allergen and mitogen after hyposensitization in asthmatic children. J Allergy Clin Immunol 1984;74:34–40.
44.
Akdis CA, Blesken T, Akdis M, Wüthrich B, Blaser K: Role of interleukin 10 in specific immunotherapy. J Clin Invest 1998;102:98–106.
45.
Bellinghausen I, Metz G, Enk A, Christmann S, Knop J, Saloga J: Insect venom immunotherapy induces interleukin–10 production and a Th1–to–Th2 shift, and changes surface marker expression in venom–allergic subjects. Eur J Immunol 1997;27:1131–1139.
46.
De Waal Malefyt R, Abrams J, Bennett B, Fidgor CG, DeVries JE: Interleukin 10 (IL–10) inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL–10 produced by monocytes. J Exp Med 1991; 174:1209–1220.
47.
Del Prete GM, De Carli M, Almerigogna F, Guidizi MG, Biagiotti R, Romagnani S: Human IL–10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen–specific proliferation and cytokine production. J Immunol 1993;150: 353–360.
48.
Ebner C, Schenk S, Najafian N, Siemann U, Fischer G, Hoffmann K, Szépfalusi Z, Scheiner O, Kraft D: T cell clones (TCC) from non–allergic individuals recognize the same epitopes of Bet v 1, the major birch pollen allergen, as TCC from atopic patients. J Immunol 1995;154:1932–1940.
49.
Punnonen JR, De Waal Malefyt R, Van Vlasselaer P, Gauchat JF, DeVries JE: IL–10 and viral IL–10 prevent IL–4–induced IgE synthesis by inhibiting the accessory cell function of monocytes. J Immunol 1993;151:1280–1289.
50.
Enk AH, Saloga J, Becker D, Mohamadzadeh M, Knop J: Induction of hapten–specific tolerance by interleukin–10 in vivo. J Exp Med 1994;179:1397–1402.
51.
Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, DeVries JE, Roncarolo MG: A CD4+ T cell–subset inhibits antigen–specific T cell responses and prevents colitis. Nature 1997;389:737–742.
52.
Brunner T, Heusser CH, Dahinden CA: Human peripheral blood basophils primed with interleukin–3 (IL–3) produce IL–4 in response to immunoglobulin E receptor stimulation. J Exp Med 1993;177:605–611.
53.
Furin MJ, Norman PS, Creticos PS, Proud D, Kagey–Sobotka A, Lichtenstein LM, Naclerio RM: Immunotherapy decreases antigen–induced eosinophil migration into the nasal cavity. J Allergy Clin Immunol 1991;88:27–32.
54.
Rak S, Roehagen O, Venge P: The effect of immunotherapy and bronchial hyperresponsiveness and eosinophil cationic protein in pollen–allergic patients. J Allergy Clin Immunol 1988; 82:470–480.
55.
Creticos PS, Atkinson NF Jr, Kagey–Sobotka A, Proud D, Meier HL, Naclerio RM, Lichtenstein LM: Nasal challenge with ragweed pollen in hay fever patients. Effect of immunotherapy. J Clin Invest 1985;76:2247– 2253.
56.
Otsuka H, Mezawa A, Oshini M, Okubo K, Seki H, Okuda M: Changes in metachromatic cells during allergen immunotherapy. Clin Exp Allergy 1991;21:115–119.
57.
Steiberger P, Bohle B, Padova DF, Wrann M, Liehl E, Scheiner O, Kraft D, Valenta R: Allergen–specific IgE production of committed B cells from allergic patients in vitro. J Allergy Clin Immunol 1995;96:209–218.
58.
Ferreira F, Hirthenlehner K, Jilek A, Godnic–Cvar J, Breiteneder H, Grimm R, Hoffmann–Sommergruber K, Scheiner O, Kraft D, Breitenbach M, Rheinberger HJ, Ebner C: Dissection of immunoglobulin E and T lymphocyte reactivity of isoforms of the major birch pollen allergen Bet v 1: Potential use of hypoallergenic isoforms for immunotherapy. J Exp Med 1996;183:599–609.
59.
Ferreira F, Ebner C, Kramer B, Casari G, Briza P, Kungl AJ, Grimm R, Jahn–Schmid B, Breiteneder H, Kraft D, Breitenbach M, Rheinberger HJ, Scheiner O: Modulation of IgE reactivity of allergens by site–directed mutagenesis: Potential use of hypoallergenic variants for immunotherapy. FASEB J 1998;12: 231–242.
60.
Nicodemus C, Philpi G, Jones N, Hirani S, Norman P: Integrated clinical experience with tolerogenic peptides. Int Arch Allergy Immunol 1997;113:326–328.
61.
Jahn–Schmid B, Siemann U, Zenker A, Bohle B, Messner P, Unger FM, Sleytr UB, Scheiner O, Kraft D, Ebner C: Bet v 1, the major birch pollen allergen, conjugated to crystalline bacterial cell surface proteins, expands allergen–specific T cells of the Th1/Th0 phenotype in vitro by induction of IL–12. Int Immunol 1997; 9:1867–1873.
62.
Goodman JS, Van Uden JH, Kobayasi H, Broide D, Raz E: DNA immunotherpeutics: New potential treatment modalities for allergic disease. Int Arch Allergy immunol 1998; 116:177–186.
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