THE ALLERGIC RESPONSE
Before discussing biomarkers in allergen immunotherapy, the putative immunological mechanisms are summarized (Fig. 1). The exposure of cedar allergen in the nose, eyes, or bronchi of genetically susceptible individuals causes Th2-deviated immune responses. Cytokines such as IL-4, IL-5, IL-9, and IL-13 derived from Th2 cells are responsible for specific IgE production, differentiation and activation of effector cells such as mast cells, basophils, and eosinophils, and direct stimulation of responder organs including mucus glands and vascular cells in the affected organ. Upon re-exposure to the allergen in the season, IgE-dependent activation of mast cells and basophils results in release of numerous mediators including histamine, cysteinyl leukotrienes, prostaglandins, and platelet activating factor, leading to sneeze, pruritus, waterly discharge, stuffy nose, and sometimes bronchospasm. In addition, mast cells and basophils, are large producers of Th2 and proinflammatory cytokines including IL-4 and TNF-α to potentiate chronic Th2-deviated inflammation in the tissue.
Allergen immunotherapy has potential to inhibit or reverse each step of the above allergic responses and to confer tolerance to the allergen (Fig. 1). Significantly higher amount of allergen is administered in immunotherapy compared to natural exposure. Because it has been shown that deviation to Th2 as expressed by IgE production depends on the allergen dose used to prime the corresponding experimental systems,16-18 where low allergen doses favor and high allergen dose suppress IgE production. In fact, clinical efficacy is related to the allergen dose,19, 20 higher doses results in better protection.
MECHANISMS OF IMMUNOTHERAPY IN THE EFFECTOR PHASE
Recently, time course analysis of clinical and immunologic measurements during the first year of grass pollen immunotherapy21 has been reported, which could substantiate a number of partial information previously observed. The first change was reduction of late phase responses (LPR) to intradermal challenge testing that was observed as early as after the first 2 weeks during up-dosing stage of the conventional injection immunotherapy. Then, elevation of specific IgG4, inhibition of basophil histamine release, and inhibition of binding of allergen-IgE complex to B cells were observed during 6 to 8 weeks at maintenance allergen doses. Reduction of early skin responses, which usually associates with clinical efficacy, was accompanied with these later immunological changes. The investigators also found that allergen-induced IL-10 production from peripheral blood mononuclear cells was a very early event accompanied with LPR suppression. They concluded that IgG responses may be necessary for clinical protection, inhibition of histamine release and allergen/IgE binding to B cells, but that the preceding IL-10 production could contribute to this process.
MECHANISM OF IMMUNOTHERAPY IN T CELL DIFFERENTIATION
The important upstream events that immunotherapy bring about in immune responses to allergen is T cell differentiation, a critical step in regulating downstream effector mechanisms. Cumulative evidence revealed that Th1 cells and T regulatory cells are the key cells in this context.
First, in patients who received grass pollen immunotherapy, increase in cells expressing IFN-γ mRNA were found in the nasal mucosa during allergen-induced late responses and the number of the cells and symptoms scores were inversely correlated.22 IL-12 is known to be a major cytokine to induce IFN-γ-producing Th1 cells and significant increases in allergen-induced IL-12 mRNA+ cells in cutaneous biopsy specimens was observed in the immunotherapy-treated patients and IL-12+ cells correlated positively with IFN-γ+ cells, inversely with IL-4+ cells.23 In terms of Th2 cells, seasonal increases in IL-5 and IL-9-expressing cells in the nasal mucosa were significantly inhibited in immunotherapy patients.24, 25 Collectively, Th1 cells are induced and Th1/Th2 balance is altered in favor of Th1 cells by immunotherapy.
There are several subsets of T regulatory cells26 and there exists inappropriate balance between allergen activation of regulatory T cells and effector Th2 cells in allergy. It was reported that CD4+CD25+ T cells, so-called naturally occurring regulatory T cells (nTreg), from non-allergic donors suppressed proliferation and IL-5 production by their own allergen-stimulated CD4+CD25- cells while the inhibition by CD4+CD25+ T cells from allergy patients were significantly reduced.27 For these conditions, immunotherapy induces regulatory T cells in the treated patients, so called inducible regulatory T cells (Tr1 cells) and many studies have constantly identified induced expression of IL-10.21, 28-30 One report demonstrated that local increases in IL-10 mRNA and protein-positive cells were observed in the nasal mucosa from patients after 2 years of grass pollen immunotherapy. The changes were observed in treated patients only during the pollen season, not during off-season, nor in placebo-treated subjects and healthy controls.30 These results suggest that IL-10 responses are allergen-specific, inducible phenomenon. IL-10 acts on B cells to induce production of IgG4.31 IL-10-induced "blocking" IgG4 inhibits mast cell histamine release and IgE-facilitated allergen-binding to B cells. IL-10 also directly blocks IgE-mediated mast cell activation.32 Further, IL-10 blocks T cell activation by inhibiting costimulatory molecule CD28 signaling pathway,33 leading to reduction in cytokines such as IL-534 and reduction in inflammatory cell recruitment such as eosinophils.24
Kaneko Y, Motohashi Y, Nakamura H, Endo T, Eboshida A. Increasing prevalence of Japanese cedar pollinosis: a meta-regression analysis. Int Arch Allergy Immunol 2005; 136: 365-71.
Ozasa K, Hama T, Dejima K et al. A 13-year study of Japanese cedar pollinosis in Japanese schoolchildren. Allergol Int 2008; 57: 175-80.
Nishima S, Chisaka H, Fujiwara T et al. Surveys on the prevalence of pediatric bronchial asthma in Japan: A comparison between the 1982, 1992, and 2002 surveys conducted in the same region using the same methodology. Allergol Int 2009; 58: 37-53.
Okubo K, Gotoh M. Inhibition of the antigen provoked nasal reaction by second-generation antihistamines in patients with Japanese cedar pollinosis. Allergol Int 2006; 55: 261-9.
Okubo K, Gotoh M, Shimada K, Ritsu M, Okuda M, Crawford B. Fexofenadine improves the quality of life and work productivity in Japanese patients with seasonal allergic rhinitis during the peak cedar pollinosis season. Int Arch Allergy Immunol 2005; 136: 148-54.
Nishiike S, Ogino S, Irifune M et al. Measurement of quality of life during different clinical phases of Japanese cedar pollinosis. Auris Nasus Larynx 2004; 31: 135-9.
Durham SR, Walker SM, Varga EM et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999; 341: 468-75.
Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 2006; 61: 198-201.
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: 1392-7.
Des Roches A, Paradis L, Menardo JL, 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: 450-3.
Jacobsen L, Niggemann B, Dreborg S et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 2007; 62: 943-8.
Okuda M. [A long-term follow-up study after discontinuation of immunotherapy for Japanese cedar pollinosis]. Arerugi 2006; 55: 655-61.
Mukai K, Obata K, Tsujimura Y, Karasuyama H. New insights into the roles for basophils in acute and chronic allergy. Allergol Int 2009; 58: 11-9.
Wilson DR, Irani AM, Walker SM et al. Grass pollen immunotherapy inhibits seasonal increases in basophils and eosinophils in the nasal epithelium. Clin Exp Allergy 2001; 31: 1705-13.
Yamaguchi M, Koketsu R, Suzukawa M, Kawakami A, Iikura M. Human basophils and cytokines/chemokines. Allergol Int 2009; 58: 1-10.
Ruedl C, Bachmann MF, Kopf M. The antigen dose determines T helper subset development by regulation of CD40 ligand. Eur J Immunol 2000; 30: 2056-64.
Von Garnier C, Astori M, Kettner A, Dufour N, Corradin G, Spertini F. In vivo kinetics of the immunoglobulin E response to allergen: bystander effect of coimmunization and relationship with anaphylaxis. Clin Exp Allergy 2002; 32: 401-10.
Blaser K. Allergen dose dependent cytokine production regulates specific IgE and IgG antibody production. Adv Exp Med Biol 1996; 409: 295-303.
Haugaard L, Dahl R, Jacobsen L. A controlled dose-response study of immunotherapy with standardized, partially purified extract of house dust mite: clinical efficacy and side effects. J Allergy Clin Immunol 1993; 91: 709-22.
Frew AJ, Powell RJ, Corrigan CJ, Durham SR. Efficacy and safety of specific immunotherapy with SQ allergen extract in treatment-resistant seasonal allergic rhinoconjunctivitis. J Allergy Clin Immunol 2006; 117: 319-25.
Francis JN, James LK, Paraskevopoulos G et al. Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J Allergy Clin Immunol 2008; 121: 1120-5.e2.
Durham SR, Ying S, Varney VA et al. 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-gamma. J Allergy Clin Immunol 1996; 97: 1356-65.
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: 254-60.
Wilson DR, Nouri-Aria KT, Walker SM et al. Grass pollen immunotherapy: symptomatic improvement correlates with reductions in eosinophils and IL-5 mRNA expression in the nasal mucosa during the pollen season. J Allergy Clin Immunol 2001; 107: 971-6.
Nouri-Aria KT, Pilette C, Jacobson MR, Watanabe H, Durham SR. IL-9 and c-Kit+ mast cells in allergic rhinitis during seasonal allergen exposure: effect of immunotherapy. J Allergy Clin Immunol 2005; 116: 73-9.
Shevach EM. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006; 25: 195-201.
Ling EM, Smith T, Nguyen XD et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 2004; 363: 608-15.
Bellinghausen I, Metz G, Enk AH, Christmann S, Knop J, Saloga J. Insect venom immunotherapy induces interleukin-10 production and a Th2-to-Th1 shift, and changes surface marker expression in venom-allergic subjects. Eur J Immunol 1997; 27: 1131-9.
Jutel M, Akdis M, Budak F et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003; 33: 1205-14.
Nouri-Aria KT, Wachholz PA, Francis JN et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J Immunol 2004; 172: 3252-9.
Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 1998; 160: 3555-61.
Royer B, Varadaradjalou S, Saas P, Guillosson JJ, Kantelip JP, Arock M. Inhibition of IgE-induced activation of human mast cells by IL-10. Clin Exp Allergy 2001; 31: 694-704.
Akdis CA, Joss A, Akdis M, Faith A, Blaser K. A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. FASEB J 2000; 14: 1666-8.
Francis JN, Till SJ, Durham SR. Induction of IL-10+CD4+CD25+ T cells by grass pollen immunotherapy. J Allergy Clin Immunol 2003; 111: 1255-61.
Kruse S, Kuehr J, Moseler M et al. Polymorphisms in the IL 18 gene are associated with specific sensitization to common allergens and allergic rhinitis. J Allergy Clin Immunol 2003; 111: 117-22.
Reif DM, McKinney BA, Motsinger AA et al. Genetic basis for adverse events after smallpox vaccination. J Infect Dis 2008; 198: 16-22.
Benjaponpitak S, Oro A, Maguire P, Marinkovich V, DeKruyff RH, Umetsu DT. The kinetics of change in cytokine production by CD4 T cells during conventional allergen immunotherapy. J Allergy Clin Immunol 1999; 103: 468-75.
Wachholz PA, Nouri-Aria KT, Wilson DR et al. Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1: Th2 cytokine ratios. Immunology 2002; 105: 56-62.
Shamji MH, Wilcock LK, Wachholz PA et al. The IgE-facilitated allergen binding (FAB) assay: validation of a novel flow-cytometric based method for the detection of inhibitory antibody responses. J Immunol Methods 2006; 317: 71-9.
Klunker S, Saggar LR, Seyfert-Margolis V et al. Combination treatment with omalizumab and rush immunotherapy for ragweed-induced allergic rhinitis: Inhibition of IgE-facilitated allergen binding. J Allergy Clin Immunol 2007; 120: 688-95.
Marone G, Triggiani M, de Paulis A. Mast cells and basophils: friends as well as foes in bronchial asthma? Trends Immunol 2005; 26: 25-31.
Narita M, Goji J, Nakamura H, Sano K. Molecular cloning, expression, and localization of a brain-specific phosphodiesterase I/nucleotide pyrophosphatase (PD-I alpha) from rat brain. J Biol Chem 1994; 269: 28235-42.
Buhring HJ, Streble A, Valent P. The basophil-specific ectoenzyme E-NPP3 (CD203c) as a marker for cell activation and allergy diagnosis. Int Arch Allergy Immunol 2004; 133: 317-29.
Buhring HJ, Simmons PJ, Pudney M et al. The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multipotent and unipotent progenitors. Blood 1999; 94: 2343-56.
Buhring HJ, Seiffert M, Giesert C et al. The basophil activation marker defined by antibody 97A6 is identical to the ectonucleotide pyrophosphatase/phosphodiesterase 3. Blood 2001; 97: 3303-5.
Nagata K, Hirai H, Tanaka K et al. CRTH2, an orphan receptor of T-helper-2-cells, is expressed on basophils and eosinophils and responds to mast cell-derived factor(s). FEBS Lett 1999; 459: 195-9.
Hirai H, Tanaka K, Yoshie O et al. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med 2001; 193: 255-61.
Platz IJ, Binder M, Marxer A, Lischka G, Valent P, Buhring HJ. Hymenoptera-venom-induced upregulation of the basophil activation marker ecto-nucleotide pyrophosphatase/phosphodiesterase 3 in sensitized individuals. Int Arch Allergy Immunol 2001; 126: 335-42.
Nagao M, Hiraguchi Y, Hosoki K et al. Allergen-induced basophil CD203c expression as a biomarker for rush immunotherapy in patients with Japanese cedar pollinosis. Int Arch Allergy Immunol 2008; 146(Suppl 1): 47-53.
Nishi H, Nishimura S, Higashiura M et al. A new method for histamine release from purified peripheral blood basophils using monoclonal antibody-coated magnetic beads. J Immunol Methods 2000; 240: 39-46.
Kawakami A, Koketsu R, Suzukawa M et al. Blocking antibody is generated in allergic rhinitis patients during specific immunotherapy using standardized Japanese cedar pollen extract. Int Arch Allergy Immunol 2008; 146(Suppl 1): 54-60.
Komata T, Soderstrom L, Borres MP, Tachimoto H, Ebisawa M. The predictive relationship of food-specific serum IgE concentrations to challenge outcomes for egg and milk varies by patient age. J Allergy Clin Immunol 2007; 119: 1272-4.
Tokuda R, Nagao M, Hiraguchi Y et al. Antigen-induced expression of CD203c on basophils predicts IgE-mediated wheat allergy. Allergol Int 2009; 58: 193-9.
Okubo K, Gotoh M, Fujieda S et al. A randomized double-blind comparative study of sublingual immunotherapy for cedar pollinosis. Allergol Int 2008; 57: 265-75.