INTRODUCTION — Allergen immunotherapy (AIT) is the only disease-modifying treatment available for several common allergic diseases. Subcutaneous immunotherapy (SCIT) is the best studied form of AIT and is effective for allergic rhinitis and rhinoconjunctivitis, allergic asthma, and Hymenoptera venom allergy. SCIT involves the repeated subcutaneous injection of increasing amounts of allergen beginning with very small doses of allergen and gradually increasing to higher doses. Another popular method of AIT involves sublingual administration in the form of dissolvable tablets or extracts. This topic will discuss the known immunologic changes that occur during AIT. Other topics related to AIT are found separately:
Allergen immunotherapy during the coronavirus pandemic — AIT is one of the most important treatment modalities for patients with for immunoglobulin (Ig)E-mediated respiratory allergies. The European Academy of Allergy and Clinical Immunology (EAACI) has drafted recommendations regarding AIT during the coronavirus disease 2019 (COVID-19) pandemic , which are accessible separately. (See 'Society guideline links' below.)
The EAACI-Allergic Rhinitis and its Impact on Asthma (ARIA) statement for AIT recommend that patients experiencing an acute respiratory tract infection of unidentified etiology or confirmed COVID-19 should temporarily discontinue AIT treatment until the infection is resolved. Confirmed cases should discontinue AIT, both SCIT or sublingual immunotherapy (SLIT), independent of disease severity until the symptoms have completely resolved and/or an adequate quarantine has been performed. The possibility of expanding injection intervals in the continuation phase should be considered. In patients who recovered from COVID-19 or who are found to have a sufficient severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody response after (asymptomatic) disease, AIT can be started or continued as planned. AIT can also be continued as usual in patients without clinical symptoms and signs of COVID-19 or other infections and without a history of exposure of SARS-CoV-2 or contact to COVID-19-confirmed individuals within the past 14 days. SLIT offers the possibility of taking it at home, thus avoiding the need to travel to an allergy clinic or doctor's office, to reduce the risk of infection.
OVERVIEW — AIT alters the immune system's reaction to causative allergens and induces long-lasting tolerance to these allergens. Subcutaneous immunotherapy (SCIT) has been in clinical use for over a century. Despite extensive experience with this therapy and decades of research, the mechanisms responsible for clinical improvement have not been fully revealed. Although less research has been done on sublingual immunotherapy (SLIT) compared with SCIT, existing studies suggest that both forms of immunotherapy induce similar immunologic changes [2-4].
The immunologic changes that take place during AIT can be grouped into four interrelated areas (figure 1). Multiple cell types in the blood and affected organs show changes and contribute to the development of allergen-specific immune tolerance . Although there is significant variation between donors and studies, the following changes are consistently observed:
●Decreases in mast cell and basophil activity and degranulation leading to fewer allergic symptoms upon allergen exposure (see 'Altered responses to allergen challenge' below). In ultra-rush AIT, these changes occur within hours, although the time course of desensitization of basophils and mast cells during more protracted drug desensitizations and traditional AIT is not as well-understood.
●Changes in allergen-specific antibody isotypes. There is an early increase in allergen-specific immunoglobulin (Ig)E levels, which later decreases. There is an early and continuous increase in allergen-specific IgG4 levels. (See 'Changes in allergen-specific antibodies' below.)
●The generation of allergen-specific regulatory T and B cells (Tregs and Bregs) and suppression of allergen-specific effector T cell subsets and innate lymphoid cells. (See 'B cell changes' below and 'T cell changes' below and 'Regulation of innate lymphoid cells' below.)
●Decreases in tissue mast cells and eosinophils, which is accompanied by a decrease in type I skin test reactivity. This occurs over months of AIT. (See 'Changes in tissue cellularity' below.)
Subcutaneous versus sublingual — SLIT and SCIT induce immune tolerance to allergens through similar mechanisms. Oral mucosa and tonsil immunity are important during SLIT because allergens are mostly captured by tolerogenic dendritic cells before reaching mast cells. The clinically evident changes occur earlier with SCIT, and SCIT generates more pronounced allergen-specific IgG4 responses compared with SLIT.
CLINICALLY EVIDENT CHANGES
Altered responses to allergen challenge — Allergic patients who are challenged with an aeroallergen to which they are sensitive often display a biphasic inflammatory response. The biphasic response consists of an early phase of symptoms that develops within minutes of challenge and, in some but not all patients, a later phase that begins several hours later. Biphasic responses are observed after both nasal and bronchial challenges, and a similar phenomenon can be seen in the skin after allergen testing. Nasal challenges are often used as a model for studying the effects of immunotherapy on both clinical symptoms and cellular events .
The early phase corresponds with the release of various mediators from local tissue mast cells and circulating basophils, including histamine, prostaglandin D2, kinins, cysteinyl leukotrienes C4, D4 and E4 (LTC4, LTD4, and LTE4), cytokines, and chemokines. In patients with allergic rhinitis, these mediators can be measured in nasal secretions during nasal challenges. Some of the mediators stimulate cell recruitment to the area of challenge, leading to a secondary influx of inflammatory cells, including T cells, eosinophils, and additional basophils. The newly arrived cells release specific inflammatory mediators that perpetuate the underlying inflammation and contribute to persistent allergic symptoms.
Traditional immunotherapy — After several months of AIT, patients undergoing nasal allergen challenge demonstrate a significantly blunted early response, although complete inhibition is uncommon. The late-phase reaction is even more effectively reduced [6,7]. However, the mechanisms by which AIT modifies and suppresses immune responses of mast cells and basophils over months of treatment is not fully understood.
Rapid desensitization protocols — In a study of rush immunotherapy, repetitive administration of increasing allergen doses over the course of a few hours during the build-up phase appeared to lead to exhaustion of stored mediators due to repetitive stimulation and release (ie, tachyphylaxis) . This mechanism of early desensitization of Fc-epsilon-RI-bearing mast cells and basophils may differ from that of traditional AIT and appears to be similar to that in rapid drug desensitization.
Histamine is one of the main mediators released upon Fc-epsilon-RI-mediated activation of these cells, and it exerts its functions through histamine receptors (HRs). Rapid upregulation of histamine 2 receptors (HR2s) on basophils was observed within the first six hours of the build-up phase of venom immunotherapy (VIT) . This upregulation strongly suppressed Fc-epsilon-RI-induced activation and mediator release of basophils in vitro, including histamine and sulfidopeptide leukotrienes, as well as cytokine production. A detailed understanding of these pathways would potentially lead to therapeutic interventions, particularly in patients with severe side effects or increased risk for anaphylactic reactions during VIT, as well as in patients with diseases in which unwanted effector cell hyper-responsiveness represents a severe and intractable pathogenetic factor.
Changes in skin test reactivity — Repeat skin testing is not recommended for monitoring the effectiveness of SCIT, because although immunotherapy can inhibit both the immediate and late responses to intradermal allergen skin testing [10,11], changes in skin reactivity as assessed with office-based skin testing do not always correlate with improvement in symptoms of allergic rhinitis or asthma. However, in research protocols, changes in skin sensitivity can generally be demonstrated with careful dose titration. (See "Overview of skin testing for IgE-mediated allergic disease", section on 'End-point dilution technique'.)
IMMUNOLOGIC CHANGES WITH SCIT
Changes in allergen-specific antibodies — Subcutaneous immunotherapy (SCIT) characteristically results in changes in several types of allergen-specific antibodies (figure 2):
●Allergen-specific IgE levels in serum initially increase then decrease slowly.
●Allergen-specific IgG levels in serum increase and remain elevated, beginning several weeks to months after the changes in IgE.
●Allergen-specific IgG4 levels continuously increase as long as SCIT continues.
●Allergen-specific IgA levels in the serum and secretions increase.
Studies of the immunologic effects of sublingual immunotherapy (SLIT) are limited. The changes that result from SLIT resemble those observed with SCIT but to a lesser extent in terms of efficacy and not all of the changes described above have been demonstrated.
IgE — The efficacy of SCIT is not dependent upon simple reductions in levels of allergen-specific IgE, and clinical improvement develops before specific IgE antibody levels decrease.
Allergen-specific IgE antibody levels initially increase in most patients and may continue to rise, even after the maximum prescribed dose has been reached. This trend reverses over time in some patients, with levels gradually decreasing within several months after reaching maintenance (ie, reaching the maximal allergen dose and continuing at that dose) (figure 2) [12-14]. Levels may even drop to below pretreatment levels. However, in other patients, there is no appreciable decline in allergen-specific IgE, which remains elevated as long as SCIT is continued. The changes that occur after SCIT is discontinued have not been studied.
Allergen-specific IgE levels typically increase after seasonal allergen exposure in individuals not receiving SCIT. This post-seasonal spike is reduced or eliminated by SCIT [12-14].
Although regulatory mechanisms start within days, a significant decrease in IgE occurs over years. This discrepancy has been attributed to reduced numbers of IgE-producing plasma cells in the bone marrow, which have very long lifespans. These cells could serve as a target for the development of other forms of immunomodulation in the future .
IgG — Allergen-specific serum IgG antibodies are often present at low levels in allergic patients. Immunotherapy generally results in an increase in allergen-specific IgG antibodies, which lags behind the rise in IgE antibodies by weeks to a few months. Levels may continue to rise over many months of maintenance immunotherapy, and elevated levels may persist for many years after immunotherapy is discontinued .
Studies demonstrate that high levels of allergen-specific IgG as a result of SCIT correlate with the dose of allergen that has been administered but not necessarily with clinical relief of symptoms . However, the failure to produce allergen-specific IgG in an individual patient receiving immunotherapy does correlate with a lack of clinical response .
Although practices differ around the world, in North America, allergen-specific IgG is used mostly as a research tool and is not routinely measured by most clinicians in the clinical practice setting, based on practice guidelines. In contrast, the author measures allergen-specific IgG prior to administration of AIT in patients who have undergone AIT in the past and finds this information can be used clinically to assess the efficacy of a patient's previous immunotherapy. For example, if the patient reports that a previous course of immunotherapy did not seem to help, the finding of low allergen-specific IgG levels to the allergen given essentially confirms that the therapy was not effective.
"Blocking" IgG4 — Before starting SCIT, allergic patients demonstrate allergen-specific IgG in serum that consists mostly of the isotypes IgG1 or IgG2. With immunotherapy, IgG4 becomes more prominent, a pattern that is called the "modified T helper type 2 (Th2) response." Specific IgG antibodies (both IgG4 and other isotypes) are capable of blocking in vitro mediator releases from allergen-stimulated mast cells and basophils (the early-phase response) and are sometimes referred to as "blocking" antibodies for this reason [12-14,17]. IgG4 may be functionally monovalent and therefore more effective as a blocking antibody than other IgG isotypes [18,19].
A protective role for allergen-specific IgG4 antibodies is also suggested by the finding that beekeepers who develop immunity after multiple stings have high levels of venom-specific IgG4 [18,20]. In contrast, individuals who have been stung only a few times typically have mostly IgG1 antibodies to venom. Thus, it may be that chronic stimulation with allergen induces a predominantly IgG4 response, while limited allergen exposure results in an IgG1-dominated response.
Precisely how IgG4 modifies the allergic response is an area of ongoing research. The two leading theories are:
●Allergen-specific IgG4 molecules may compete for allergen with IgE bound to mast cells (ie, the blocking antibody theory). However, the steps subsequent to the binding of allergen to IgG4 have not been defined . IgG4 displays unique structural features of its hinge region that results in a lower affinity for certain Fc receptors. Particularly, the ability of a dynamic Fab arm exchange, which leads to bispecific antibodies that are functionally monomeric, significantly decreases the possibility for cross-linking by allergens and enhances the allergen-blocking activity .
●Allergen-specific IgG4 may reduce the sensitivity of antigen-presenting B cells and therefore T cells to allergen by competing with IgE in a mechanism called "IgE-facilitated antigen (or allergen) presentation" . IgE-facilitated antigen presentation refers to the observation that antigen-presenting B cells with the low-affinity IgE receptor CD23 can be activated by low levels of allergen in the presence of allergen-specific IgE . However, if IgG4 is added, the amount of allergen required to activate the B cell becomes much greater, presumedly because IgG4 competes with IgE. This attenuated antigen presentation then interferes with the activation of T cells.
IgG4 may also have anti-inflammatory properties because it does not stimulate the activation of the complement cascade and is capable of inhibiting immune complex formation by other IgG subtypes .
Measuring IgG4 levels has been proposed to be a good indicator of clinical efficacy of AIT during follow-up, although this is largely confined to research settings [23,24]. In a retrospective review of 17 immunotherapy studies, serum-specific IgG and IgG4 levels increased after 8 weeks of a cluster up-dosing schedule, 16 weeks of a conventional up-dosing schedule, and after a second cycle of pre-seasonal pollen allergoid SCIT. The IgG changes correlated with an increase in the inhibitory activity of patients' serum measured by the cellular antigen stimulation test . Grass pollen SCIT has reduced seasonal increases in serum allergen-specific IgE, whereas 60- to 80-fold increases in allergen-specific IgG and 100-fold increases in allergen-specific IgG4 have been observed.
A study of immunologic changes in patients undergoing grass pollen SLIT demonstrated a rapid and continuing increase in ryegrass pollen (RGP)-specific serum IgG4, accompanied by an increase in the frequency of peripheral blood IgG4+ memory B cells. During the course of SLIT, a similar increase in RGP-specific IgG2 was observed in serum, corresponding with increased frequency of IgG2+ memory B cells in the blood. Although the antigen specificity of IgG4+ or IgG2+ memory cells from peripheral blood were not studied, there was a close correlation with the RGP-specific serum IgG4 or IgG2 .
Other changes in IgG — SCIT alters other properties of allergen-specific IgG antibodies, such as their specificity (ie, the set of epitopes on allergens that are recognized by antibodies) and avidity (ie, the collective strength of the interactions of antigens and antibodies within an antiserum). This was demonstrated in a study of ultra-rush insect venom immunotherapy (VIT), in which changes in IgG specificity to the major bee venom allergen, phospholipase A2, were analyzed . Within 12 hours of starting therapy, the patients' specificity patterns came to resemble those of healthy nonallergic individuals, and the highest avidity antibody fractions were reduced. This preceded the increase in IgG titers [26,27].
IgA — Immunotherapy results in an increase in allergen-specific IgA in the serum and in secretions. The clinical significance of this is unclear, although one study suggested that the isotype IgA2 may function as blocking antibody at the mucosal surface [28,29]. In a study of house dust mite (HDM) SCIT, the frequencies of allergen-specific IgA+ and IgG4+ B cells increased during treatment. They were higher in therapy responders compared with nonresponders. The increase in allergen-specific IgA+ B cells were significant after 10 weeks of treatment and, for IgG4+ cells, after 30 weeks of treatment. Corresponding increases in serum levels of allergen-specific IgA and IgG4 were also demonstrated in responders .
B cell changes — There is growing evidence that SCIT induces IgG4-positive regulatory B cells (Bregs) that produce high levels of interleukin (IL-)10 and suppress antigen-specific T cell proliferation [2,20]. In a study comparing immunologic findings in nonallergic beekeepers and allergic patients before and after VIT, highly purified IL-10-secreting Bregs (BR1) were phenotypically and functionally characterized . B cells specific for the major bee venom allergen phospholipase A2 were isolated from each group of patients. Human IL-10+ BR1 cells expressed high surface CD25 and CD71 levels and low CD73 levels. Sorting of CD73-CD25+CD71+ B cells allowed enrichment of human BR1 cells, which produced high levels of IL-10 and vigorously suppressed antigen-specific CD4+ T cell proliferation. Thus, BR1 cells can give rise to IgG4-producing plasma cells.
In addition to IL-10, IL-1 receptor antagonist (IL-1RA), a cytokine that prevents the binding of IL-1-alpha and IL-1-beta to their receptor, was expressed by CD73-CD25+CD71+ B regulatory cells in a study of house dust mite (HDM) SCIT . IL-1RA reduces the inflammation related to IL-1 in patients with various diseases. The number of plasmablasts and IL-10- and IL-1RA-producing Breg cells expanded during HDM-SCIT and were higher in responders compared with nonresponders. The frequencies of allergen-specific IgG4+ B cells, plasmablasts, and IL-10+ and/or IL-1RA+ Breg cells positively correlated with improved clinical response during SCIT .
Role of IL-10 — Interleukin 10 is the leading cytokine produced by regulatory T cells (Tregs) during interactions with B cells that suppress specific IgE production, and IL-10 also induces specific IgG4 production . In addition, B cells overexpressing IL-10 potently suppressed production of proinflammatory cytokines by peripheral blood mononuclear cells and suppressed antigen-specific proliferation in vitro. These findings demonstrate an essential role for IL-10 in inducing an immunoregulatory phenotype in B cells, which exerts substantial anti-inflammatory and immunosuppressive functions . B cells and dendritic cells also interact via IL-10. IL-10-overexpressing B cells reduce the overall costimulation potential and maturation of monocyte-derived dendritic cells, conferring them with a regulatory phenotype.
T cell changes — During AIT, allergen-specific Treg cells are generated, which produce IL-10 and transforming growth factor-beta (TGF-beta), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and program cell death protein 1 (PD1) [33-38]. These cytokines suppress proliferative and cytokine responses against major allergens. IL-10 reduces proinflammatory cytokine release from mast cells, eosinophils, and T cells and elicits tolerance in T cells by means of selective inhibition of the CD28 costimulatory pathway [36,37]. The transcription factor forkhead box protein 3 (FOXP3) is required for the development and function of naturally occurring Treg cells, and its expression is sufficient to convert nonregulatory CD4+CD25+ T cells into T cells with regulatory activity . FOXP3 expression negatively correlates with levels of IgE, eosinophilia, and interferon-gamma (IFN-gamma), and the ratio of FOXP3+ T cells to total CD4+ T cells is significantly lower in patients with asthma or atopic dermatitis compared with that seen in healthy subjects .
During AIT, CD4+ T helper (Th) cells shift from producing Th2 (especially IL-4) cytokines following stimulation with allergen to producing Th1 and Treg cytokines (eg, IFN-gamma, IL-10) [36,41-43]. Increased production of IL-12, a strong inducer of Th1 responses, contributes to this shift .
Immunotherapy can result in the selective elimination of specific pathogenic Th2 subsets. One small study identified two subsets of allergen-specific Th2 cells in the peripheral blood of patients with and without alder pollen allergy . One subset of Th2 cells expressed CD27 (a costimulatory molecule in the tumor necrosis factor receptor superfamily member), and another subset did not. The CD27+ cells demonstrated high expression of IL-10 and IFN-gamma, which is indicative of active tolerogenic processes, and these cells are presumed to be protective against allergy. Nonallergic subjects monitored through a pollen season had CD27+ cells but not CD27- cells, whereas allergic patients had both types. In allergic patients undergoing specific immunotherapy, CD27- cells were dramatically deleted, while CD27+ cells remained. Thus, deletion of CD27- cells may allow the CD27+ cells to establish tolerance. It was suggested that these changes may revert when immunotherapy is discontinued.
Finally, following immunotherapy, reduced lymphoproliferative responses to allergen can be demonstrated [44,46-50].
Regulation of innate lymphoid cells — Innate lymphoid cells (ILCs) are lymphocytes that, unlike adaptive T and B cells, do not express rearranged antigen-specific receptors. ILCs are believed to play an important role in many inflammatory diseases, including allergic diseases and asthma . They may be involved in persistence and chronicity of these diseases. Type 2 ILCs in the lung play a critical role in priming the adaptive type 2 immune response to inhaled allergens, including recruitment of eosinophils and Th2 cytokine production. ILCs respond to IL-33 from epithelial cells and initiate inflammation [52,53]. Grass pollen SCIT inhibited the seasonal increase in type 2 ILCs in patients with seasonal allergic rhinitis, and suppression of these cells might contribute to the clinical and immunologic tolerance observed after SCIT . In a double-blind, placebo-controlled trial, it was shown that the ability of ILC2 to make IL-10 was repaired in patients after grass-pollen sublingual immunotherapy. IL-10 production was coming from killer cell lectin-like receptor G1 (KLRG1)+ ILC2s after IL-33 and retinoic acid stimulation . The frequency of IL-10+ KLRG1+ ILC2s were lower in patients with grass-pollen allergy in comparison to healthy subjects.
Changes in tissue cellularity — AIT decreases the recruitment of mast cells, basophils, and eosinophils in the skin, nose, eye, and bronchial mucosa after provocation or natural exposure to allergens [56-61]. For example, successful grass pollen immunotherapy was associated with inhibition of seasonal increases in basophils and eosinophils in the nasal epithelium . These changes can be observed after two years of treatment.
It has been proposed that histamine and leukotrienes are released at low subthreshold levels from mast cells and basophils during AIT. This low-level release is not sufficient to cause allergic symptoms but depletes the intracellular granules, rendering the cells resistant to activation [62-64]. Basophil expression of diamine oxidase is being studied as a biomarker of the response to AIT .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)
●Clinical changes with allergen immunotherapy (AIT) – AIT alters the abnormal immune response underlying allergic disease, although the mechanisms directly responsible for this effect are not fully defined. Clinically, both the early and late phases of symptoms and tissue inflammation after allergen challenge are blunted by AIT. Intradermal skin test results to specific allergens may also be inhibited, but these changes do not always correlate with improvement in symptoms of allergic rhinitis or asthma, and, thus, repeat skin testing is not recommended for monitoring the effectiveness of AIT. (See 'Clinically evident changes' above.)
●Allergen-specific immunoglobulins – In most patients, allergen-specific immunoglobulin (Ig)E in serum initially rises and then gradually falls. Allergen-specific IgG increases, and the dominant isotype changes from IgG1 and IgG2 to IgG4. These allergen-specific IgG antibodies can block in vitro degranulation of mast cells upon exposure to allergen and may also alter the presentation of allergen to T cells. (See 'Changes in allergen-specific antibodies' above.)
●B and T cell changes – Immunotherapy results in the generation of allergen-specific regulatory B cells and T cells (Bregs and Tregs) and suppression of allergen-specific effector T cell subsets. (See 'B cell changes' above and 'T cell changes' above.)
●Changes in tissue cellularity – AIT decreases the recruitment of mast cells, basophils, and eosinophils in the skin, nose, eye, and bronchial mucosa after provocation or natural exposure to allergens. (See 'Changes in tissue cellularity' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Philip S Norman, MD, who contributed to earlier versions of this topic review.
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