Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers
Authors: Mohamed H. Shamji, Stephen R. Durham
Journal: Journal of Allergy and Clinical Immunology (2017)

Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This disease-modifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells. Suppression of TH2 immunity can occur as a consequence of either deletion or anergy of antigen-specific T cells; induction of antigen-specific regulatory T cells; or immune deviation in favor of TH1 responses. It is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Recent data highlight the role of IL-10–producing regulatory B cells and "protective" antibodies that likely contribute to long-term tolerance. Understanding mechanisms underlying induction and persistence of tolerance should identify predictive biomarkers of clinical response and discover novel and more effective strategies for immunotherapy. Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This disease-modifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells. Suppression of TH2 immunity can occur as a consequence of either deletion or anergy of antigen-specific T cells; induction of antigen-specific regulatory T cells; or immune deviation in favor of TH1 responses. It is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Recent data highlight the role of IL-10–producing regulatory B cells and "protective" antibodies that likely contribute to long-term tolerance. Understanding mechanisms underlying induction and persistence of tolerance should identify predictive biomarkers of clinical response and discover novel and more effective strategies for immunotherapy. GlossaryBet v 1A potent allergen from trees within the order Fagales, which is the main cause of type I allergies observed in early spring and characterized by hay fever, dermatitis, and asthma.METHYLATED CpG SITESCpG sites are regions of DNA in which a cytosine nucleotide occurs next to a guanine nucleotide separated by only 1 phosphate. Methylation of the cytosine within a gene can turn the gene off.c-kit (CD117)A cytokine receptor most notably expressed on the surfaces of hematopoietic stem cells and other cell types, including mast cells. CD117 is a receptor tyrosine kinase type III protein that binds to stem cell factor and forms a dimer that activates its intrinsic tyrosine kinase, resulting in phosphorylation and activation of signal transduction molecules that produce cell signaling.CYTOTOXIC T LYMPHOCYTE–ASSOCIATED PROTEIN 4 (CTLA-4)A receptor that functions as an inhibitory signal and downregulates immune responses when bound to CD80 and CD86. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation.IFN-γA type II interferon, IFN-γ is a cytokine required for innate and adaptive immunity against viral, bacterial, and protozoal infections. IFN-γ has been shown to be an important activator of macrophages and inducer of class II MHC molecule expression. IFN-γ is produced predominantly by natural killer (NK) and NKT cells as part of the innate immune response and by CD4 TH1 and CD8 cytotoxic T lymphocyte effector T cells once antigen-specific immunity develops.ImmunoCAP (A REGISTERED TRADEMARK OF PHARMACIA DIAGNOSTICS AB)An in vitro quantitative assay that measures allergen-specific IgE levels in human serum. ImmunoCAP assays can be performed on hundreds of allergens by using cellulose polymer, which provides high binding capacity of clinically relevant allergen proteins, including those present at very low levels.IL-3A growth-promoting cytokine capable of supporting the proliferation and activation of a broad range of hematopoietic cell types, including basophils.IL-6A cytokine also known as IFN-β2 and implicated in a wide variety of inflammation-associated disease states, IL-6 has been associated with B-cell maturation and has been shown to act as an endogenous pyrogen capable of inducing fever in patients with autoimmune diseases or infections.IL-12A cytokine produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation and has been shown to be required for differentiation of naive T cells into TH1 cells.IL-21A cytokine expressed in human CD4+ T cells and found to be upregulated in TH2 and TH17 subsets and follicular T cells, which induces cell division/proliferation of various cells of the immune system, including natural killer cells and cytotoxic T cells.IL-25A proinflammatory cytokine that shares sequence similarity with IL-17 and has been shown to favor the TH2-type immune response. IL-25 can induce nuclear factor κB activation and stimulate IL-8 production.IL-33A member of the IL-1 family of cytokines expressed on TH2 cells, mast cells, and group 2 innate lymphocytes that potently drives production of TH2-associated cytokines.IL-35An IL-12 family cytokine produced by regulatory, but not effector, T and B cells that plays a role in immune suppression.PROGRAMMED CELL DEATH 1 (PD-1)A cell-surface receptor that plays an important role in downregulating the immune system and suppressing inflammatory T-cell activation. PD-1 is an immune checkpoint that serves a dual role of promoting apoptosis in antigen-specific T cells while simultaneously reducing apoptosis in regulatory T cells.THYMIC STROMAL LYMPHOPOIETIN (TSLP)A cytokine that stimulates T-cell maturation through activation of antigen-presenting cells, such as dendritic cells and macrophages.TGF-βA cytokine secreted by many cell types, including macrophages, that controls proliferation, cellular differentiation, and inflammatory processes in a variety of cells. It also plays a role in T-cell regulation and differentiation.The Editors wish to acknowledge Kristina Bielewicz, MS, for preparing this glossary. A potent allergen from trees within the order Fagales, which is the main cause of type I allergies observed in early spring and characterized by hay fever, dermatitis, and asthma. CpG sites are regions of DNA in which a cytosine nucleotide occurs next to a guanine nucleotide separated by only 1 phosphate. Methylation of the cytosine within a gene can turn the gene off. A cytokine receptor most notably expressed on the surfaces of hematopoietic stem cells and other cell types, including mast cells. CD117 is a receptor tyrosine kinase type III protein that binds to stem cell factor and forms a dimer that activates its intrinsic tyrosine kinase, resulting in phosphorylation and activation of signal transduction molecules that produce cell signaling. A receptor that functions as an inhibitory signal and downregulates immune responses when bound to CD80 and CD86. CTLA-4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation. A type II interferon, IFN-γ is a cytokine required for innate and adaptive immunity against viral, bacterial, and protozoal infections. IFN-γ has been shown to be an important activator of macrophages and inducer of class II MHC molecule expression. IFN-γ is produced predominantly by natural killer (NK) and NKT cells as part of the innate immune response and by CD4 TH1 and CD8 cytotoxic T lymphocyte effector T cells once antigen-specific immunity develops. An in vitro quantitative assay that measures allergen-specific IgE levels in human serum. ImmunoCAP assays can be performed on hundreds of allergens by using cellulose polymer, which provides high binding capacity of clinically relevant allergen proteins, including those present at very low levels. A growth-promoting cytokine capable of supporting the proliferation and activation of a broad range of hematopoietic cell types, including basophils. A cytokine also known as IFN-β2 and implicated in a wide variety of inflammation-associated disease states, IL-6 has been associated with B-cell maturation and has been shown to act as an endogenous pyrogen capable of inducing fever in patients with autoimmune diseases or infections. A cytokine produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation and has been shown to be required for differentiation of naive T cells into TH1 cells. A cytokine expressed in human CD4+ T cells and found to be upregulated in TH2 and TH17 subsets and follicular T cells, which induces cell division/proliferation of various cells of the immune system, including natural killer cells and cytotoxic T cells. A proinflammatory cytokine that shares sequence similarity with IL-17 and has been shown to favor the TH2-type immune response. IL-25 can induce nuclear factor κB activation and stimulate IL-8 production. A member of the IL-1 family of cytokines expressed on TH2 cells, mast cells, and group 2 innate lymphocytes that potently drives production of TH2-associated cytokines. An IL-12 family cytokine produced by regulatory, but not effector, T and B cells that plays a role in immune suppression. A cell-surface receptor that plays an important role in downregulating the immune system and suppressing inflammatory T-cell activation. PD-1 is an immune checkpoint that serves a dual role of promoting apoptosis in antigen-specific T cells while simultaneously reducing apoptosis in regulatory T cells. A cytokine that stimulates T-cell maturation through activation of antigen-presenting cells, such as dendritic cells and macrophages. A cytokine secreted by many cell types, including macrophages, that controls proliferation, cellular differentiation, and inflammatory processes in a variety of cells. It also plays a role in T-cell regulation and differentiation. The Editors wish to acknowledge Kristina Bielewicz, MS, for preparing this glossary. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com. Allergen immunotherapy is effective in selected patients with allergic rhinitis, including those with mild/moderate asthma.1Burks A.W. Calderon M.A. Casale T. Cox L. Demoly P. Jutel M. et al.Update on allergy immunotherapy: American Academy Of Allergy, Asthma & Immunology/European Academy Of Allergy and Clinical Immunology/PRACTALL consensus report.J Allergy Clin Immunol. 2013; 131: 1288-1296.e3Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 2Bousquet J. Lockey R. Malling H.J. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper.J Allergy Clin Immunol. 1998; 102: 558-562Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar There is heterogeneity in the populations studied, the different allergen products and protocols used, and the clinical outcomes used to document efficacy and safety.3Dhami S. Nurmatov U. Arasi S. Khan T. Asaria M. Zaman H. et al.Allergen immunotherapy for allergic rhinoconjunctivitis: a systematic review and meta-analysis.Allergy. 2017; 72: 1597-1631Crossref PubMed Scopus (22) Google Scholar Nonetheless, recent guidelines4Roberts G. Pfaar O. 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Sublingual immunotherapy involves daily drops or tablets placed under the tongue. Sublingual immunotherapy is effective and safer than subcutaneous immunotherapy, such that it is self-administered by the patient at home.1Burks A.W. Calderon M.A. Casale T. Cox L. Demoly P. Jutel M. et al.Update on allergy immunotherapy: American Academy Of Allergy, Asthma & Immunology/European Academy Of Allergy and Clinical Immunology/PRACTALL consensus report.J Allergy Clin Immunol. 2013; 131: 1288-1296.e3Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 8Canonica G.W. Cox L. Pawankar R. Baena-Cagnani C.E. Blaiss M. Bonini S. et al.Sublingual immunotherapy: World Allergy Organization position paper 2013 update.World Allergy Organ J. 2014; 7: 6Crossref PubMed Scopus (205) Google Scholar Sublingual and subcutaneous immunotherapy are effective generally within 2 to 4 months of initiating treatment and can be given presesonally/coseasonally for short-term benefit. Indirect comparisons have suggested that immunotherapy might be more effective than antiallergic drugs. In contrast to antiallergic drugs and currently available mAb therapies, when allergen immunotherapy is given continuously for 3 years, both routes have been shown to be disease-modifying, manifest as long-term remission of symptoms for at least 2 to 3 years after discontinuation.9Durham S.R. Ying S. Varney V.A. Jacobson M.R. Sudderick R.M. Mackay I.S. 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: 1356-1365Abstract Full Text Full Text PDF PubMed Google Scholar, 10Durham S.R. Emminger W. Kapp A. de Monchy J.G. Rak S. Scadding G.K. et al.SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial.J Allergy Clin Immunol. 2012; 129: 717-725.e5Abstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar In this review we explore historical and recent data on the mechanisms of immunotherapy for inhalant allergens. Our expectation is that a greater understanding of the underlying mechanisms of tolerance will identify potential biomarkers that could predict and/or monitor the response to treatment. Such knowledge could inform new potential treatment strategies. The cardinal features of allergic rhinitis include increased allergen-specific IgE concentrations to clinically relevant allergens, IgE-dependent activation of mast cells, and local eosinophilia in target organs. In addition to systemic and regional lymphatic sources of IgE, specific IgE can be synthesized and produced locally by B cells within the respiratory mucosa,11Wu Y.C. James L.K. Vander Heiden J.A. Uduman M. Durham S.R. Kleinstein S.H. et al.Influence of seasonal exposure to grass pollen on local and peripheral blood IgE repertoires in patients with allergic rhinitis.J Allergy Clin Immunol. 2014; 134: 604-612Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar thereby accounting for the occasional phenomenon of "local allergic rhinitis" with symptoms on allergen exposure in the absence of detectable serum specific IgE or positive immediate skin test results to relevant allergens.12Creticos P.S. Peters S.P. Adkinson Jr., N.F. Naclerio R.M. Hayes E.C. Norman P.S. et al.Peptide leukotriene release after antigen challenge in patients sensitive to ragweed.N Engl J Med. 1984; 310: 1626-1630Crossref PubMed Google Scholar IgE-dependent activation is detectable during the immediate (0- to 60-minute) response after nasal allergen provocation. Allergen cross-linking of adjacent surface IgE molecules on mast cells and basophils triggers within seconds or minutes the release of preformed mediators, such as histamine13Naclerio R.M. Proud D. Togias A.G. Adkinson Jr., N.F. Meyers D.A. Kagey-Sobotka A. et al.Inflammatory mediators in late antigen-induced rhinitis.N Engl J Med. 1985; 313: 65-70Crossref PubMed Google Scholar and tryptase,14Castells M. Schwartz L.B. Tryptase levels in nasal-lavage fluid as an indicator of the immediate allergic response.J Allergy Clin Immunol. 1988; 82: 348-355Abstract Full Text PDF PubMed Scopus (0) Google Scholar contained within intracytoplasmic granules. Newly formed mediators derived from arachidonic acid within the membrane lipid include sulphidopeptide leukotrienes (LTs; LTC4, LTD4, and the terminal metabolite LTE4),12Creticos P.S. Peters S.P. Adkinson Jr., N.F. Naclerio R.M. Hayes E.C. Norman P.S. et al.Peptide leukotriene release after antigen challenge in patients sensitive to ragweed.N Engl J Med. 1984; 310: 1626-1630Crossref PubMed Google Scholar platelet-activating factor, and prostaglandin D2. The biological properties of these mediators are consistent with the local vasodilatation, edema formation, local neurogenic stimulation, and mucus secretion that characterize typical nasal allergen–induced immediate type I hypersensitivity. In the lower airways bronchial smooth muscle contraction, as well as edema and mucus hypersecretion, contribute to acute bronchoconstriction. A proportion of subjects have a late response at 2 to 10 hours after challenge. The late response is characterized by tissue eosinophilia, nasal congestion, and mucosal hyperreactivity to both allergic and nonallergic triggers that can last for days or even weeks after a single nasal allergen challenge. In contrast to findings in patients with allergic asthma and nasal polyposis, morphologic and immunohistochemical features of airway remodeling are not a consistent feature of even moderate/severe allergic rhinitis.15Eifan A.O. Orban N.T. Jacobson M.R. Durham S.R. Severe persistent allergic rhinitis. inflammation but no histologic features of structural upper airway remodeling.Am J Respir Crit Care Med. 2015; 192: 1431-1439Crossref PubMed Google Scholar The above pathophysiologic events are under the regulation of a distinct subset of TH2 cells. TH2 cells produce IL-4, the key cytokine responsible for TH2 cell differentiation.16Shamji M.H. Layhadi J.A. Scadding G.W. Cheung D.K. 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IL-4 and IL-13 upregulate vascular cell adhesion protein 1 expression on the vascular endothelium, promoting adhesion of very late antigen 4, integrin α4β1–expressing eosinophils. Both stimulate mucus production from glands in the upper and lower airways. IL-5 is responsible for terminal differentiation and release of eosinophils from the bone marrow and prolongs eosinophil survival by inhibiting eosinophil apoptosis in tissues.20Wechsler M.E. Fulkerson P.C. Bochner B.S. Gauvreau G.M. Gleich G.J. Henkel T. et al.Novel targeted therapies for eosinophilic disorders.J Allergy Clin Immunol. 2012; 130: 563-571Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Along with stem cell factor, IL-9 is a key cytokine for the differentiation and maturation of mast cells.21Sehra S. Yao W. Nguyen E.T. Glosson-Byers N.L. Akhtar N. Zhou B. et al.TH9 cells are required for tissue mast cell accumulation during allergic inflammation.J Allergy Clin Immunol. 2015; 136: 433-440.e1Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar Release of TH2 cytokines and tissue eosinophilia are apparent during the late-phase response that occurs at 4 to 12 hours after allergen challenge.22Durham S.R. Ying S. Varney V.A. Jacobson M.R. Sudderick R.M. Mackay I.S. et al.Cytokine messenger RNA expression for IL-3, IL-4, IL-5, and granulocyte/macrophage-colony-stimulating factor in the nasal mucosa after local allergen provocation: relationship to tissue eosinophilia.J Immunol. 1992; 148: 2390-2394PubMed Google Scholar Group 2 innate lymphoid cells (ILC2s) represent an alternative source of TH2 cytokines in the nasal mucosa. Innate lymphoid cells (ILCs) are morphologically similar to lymphocytes, although they are distinct in not expressing surface antigen receptors or other cell lineage markers and act in an antigen-independent manner.23Spits H. Cupedo T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function.Annu Rev Immunol. 2012; 30: 647-675Crossref PubMed Scopus (399) Google Scholar, 24Artis D. Spits H. The biology of innate lymphoid cells.Nature. 2015; 517: 293-301Crossref PubMed Scopus (403) Google Scholar ILCs consist of 3 different groups referred to as group 1 ILCs, ILC2s, and group 3 ILCs. Group 1 ILCs constitutively express T-box transcription factor and produce the TH1 cytokines IFN-γ and TNF and provide protection against intracellular bacteria and parasites. ILC2s constitutively express RAR-related orphan receptor α and GATA-3; produce TH2 cytokines, particularly IL-5 and IL-13; and provide immunity to helminths, as well as stimulating allergic responses. Group 3 ILCs are characterized by the transcription factor RAR-related orphan receptor γt, express IL-17a and/or IL-22, afford protection against extracellular bacteria, and are involved in tissue repair processes. The role of ILC2s in allergic rhinitis was first identified in patients with cat allergy, who showed increases in peripheral blood ILC2 numbers at 4 hours after a cat allergen nasal challenge.25Doherty T.A. Scott D. Walford H.H. Khorram N. Lund S. 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ILC2s represent an abundant alternative source of TH2 cytokines and likely serve to amplify and maintain local TH2-driven allergic inflammation. In view of recently identified plasticity within ILC2s in tissues of patients with chronic obstructive pulmonary disease and chronic rhinosinusitis,28Bal S.M. Bernink J.H. Nagasawa M. Groot J. Shikhagaie M.M. Golebski K. et al.IL-1beta, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs.Nat Immunol. 2016; 17: 636-645Crossref PubMed Scopus (76) Google Scholar this concept must be revisited in the context of allergic rhinitis.18Matsuoka T. Shamji M.H. Durham S.R. Allergen immunotherapy and tolerance.Allergol Int. 2013; 62: 403-413Abstract Full Text PDF PubMed Scopus (34) Google Scholar Although IgE-dependent mast cell activation and tissue eosinophilia are driven by TH2 lymphocytes, TH2 cell differentiation is dependent on the local cytokine milieu provided by interactions between the respiratory epithelium, local dendritic cells (DCs), and regional lymph nodes. In an atopic subject aeroallergens pass through the inflamed nasal epithelium, and activated epithelial cells release CCL2 and CCL20, which recruit immature DCs (Fig 1, A). Activated DCs migrate to regional draining lymph nodes and polarize naive T cells into TH2 cells. DC migration is primed by IL-13 produced by ILC2s and also by IL-4 produced principally by basophils. Within the germinal center of the lymph node, a subset of TH cells differentiates into follicular helper T (TFH) cells. 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Additionally, these epithelially derived cytokines are major growth factors for ILC2s that amplify and maintain local TH2-driven allergic inflammation.34Mjosberg J. Spits H. Human innate lymphoid cells.J Allergy Clin Immunol. 2016; 138: 1265-1276Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 35Xue L. Salimi M. Panse I. Mjosberg J.M. McKenzie A.N. Spits H. et al.Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells.J Allergy Clin Immunol. 2014; 133: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 36Kouser L. Kappen J. Walton R.P. Shamji M.H. 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