Allergen Immunotherapy: Past, Present and Future — Comprehensive Notes

Overview: Global burden and clinical context

  • Allergy and related diseases are highly prevalent in westernized countries, affecting up to frac{1}{3} of the population.
  • Allergic rhinitis prevalence (physician-diagnosed) varies by age and region: 13\% in children and 14\% in adults in the USA, 23\% in adults in Europe.
  • Impact of allergic rhinitis includes impaired sleep quality, reduced work/school performance, and diminished leisure activity; frequently co-occurs with asthma.
  • Hymenoptera venom stings cause systemic reactions in about 3.4\% of children and 7.5\% of adults in Europe.
  • Food allergy: a convincing history of IgE-mediated food allergy is present in about 8\% of US children; within this, approximately 2\% are allergic to peanut.
  • Risks of anaphylaxis and fatalities associated with food and venom allergies have major implications for patient quality of life and family; current management emphasizes allergen avoidance and active immunotherapy research to modify disease processes.
  • This Perspective outlines insights from past experiences with allergen immunotherapy (AIT), mechanisms of inflammatory responses, and the development of immunotherapy-induced tolerance. It also covers routes (subcutaneous and sublingual), safety improvements, adherence, and future directions via molecular allergology and combination strategies targeting TH2 pathways.

Brief history of allergen immunotherapy

  • 1911: Leonard Noon showed that repeated injections of crude grass pollen extract into hay fever patients reduced immediate conjunctival sensitivity to grass pollen.
  • 1914: Freeman reported symptom reduction in the pollen season (rhinitis and asthma).
  • 1921: Prausnitz and Kutsner demonstrated passive transfer of immediate IgE sensitivity via serum factors (reagin/IgE).
  • 1935: Cooke and colleagues showed protective immunity after immunotherapy could be transferred passively, linking allergy reversal to transferable serum factors.
  • 1954: First double-blind trial (Frankland) confirmed efficacy of subcutaneous grass pollen injections for seasonal asthma and identified the active component as the high-molecular-weight protein portion of the allergen extract.
  • 1965: Lowell and Franklin demonstrated subcutaneous ragweed pollen extract was effective within a multi-allergen mixture.
  • 1978: Norman and Lichtenstein established that immunotherapy is allergen-specific for allergic diseases, highlighting limitations of symptomatic anti-allergic drugs.
  • 1998: WHO position paper summarized efficacy and risks of immunotherapy, noted progress in standardized extracts and emerging evidence for sublingual immunotherapy (SLIT) as a safer alternative; this was reinforced by the World Allergy Organization.
  • 1999: Reported that three years of continuous subcutaneous immunotherapy (SCIT) with grass pollen extract yielded long-term benefits that persisted for at least three years after discontinuation.
  • Venom immunotherapy established as highly effective in preventing anaphylaxis after Hymenoptera stings.
  • Over the years, randomized trials and observational studies have supported allergen-specific tolerance and long-term disease modification with immunotherapy.

Mechanisms of immunotherapy and immune tolerance

  • In atopic individuals, natural low-level exposure to environmental allergens triggers IgE-mediated mast cell activation and eosinophilic inflammation, regulated by TH2 cytokines (e.g., IL-4, IL-5, IL-9, IL-13).
  • Passive transfer experiments established that serum factors (IgE) drive immediate hypersensitivity, while allergen-induced protective immunity is linked to IgG/IgA with IgE-blocking activity.
  • Immunotherapy induces tolerogenic dendritic cells (DCs) with a pro-regulatory phenotype, leading to a cascade of regulatory components:
    • Expansion of peripherally derived regulatory T cells (pTregs) expressing IL-10, TGF-β, IL-35; and thymus-derived FOXP3+ natural Tregs.
    • Tregs migrate to circulation and nasal mucosa after pollen immunotherapy and suppress TH2 differentiation via cytokines and cell interactions.
    • IL-10 promotes isotype switching to allergen-specific IgG subclasses (notably IgG4) and IgG1; TGF-β promotes switching to IgA (IgA1/IgA2).
    • Allergen-specific IgG/IgA compete with IgE for allergen, blocking formation of allergen–IgE complexes and inhibiting IgE-mediated activation of mast cells/basophils and IgE-facilitated antigen presentation to TH2 cells, thereby dampening TH2 responses.
  • B cell and epithelial cell interactions contribute to tolerance:
    • IL-10 and TGF-β influence B cells to produce IgG1/IgG4 and IgA, respectively.
    • Epithelial cytokines (TSLP, IL-25, IL-33) drive ILC2s and TH2 responses; immunotherapy can modulate these pathways.
  • ILC2s can amplify local TH2 cytokine production; grass pollen immunotherapy reduces seasonal ILC2 expansion and can induce a distinct IL-10–secreting ILC2 subset expressing KLRG1.
  • Regulatory B cells (Breg) and regulatory T cells contribute to a network of suppression via IL-10 (and possibly IgG4). Distinct regulatory pathways may operate in different tissues (nasal mucosa vs systemic circulation).
  • For oral immunotherapy (OIT) in peanut allergy, a decrease in allergen-stimulated TH2A cells (CRTH2+CD161+CD27–) accompanies desensitization; memory effector T cell activation may occur early, but marked decreases in TH2A cells do not always coincide with peripheral Treg expansion. Local mucosal immune mechanisms (e.g., retinoic acid–dependent Treg induction) may contribute to tolerance.
  • Compared with inhalant allergens, peanut OIT yields desensitization more readily but long-term sustained unresponsiveness is less consistently achieved; mechanisms may involve persistent TH2A cell dynamics and the quality of Treg responses.

Immunotherapy for inhalant vs. food allergies: routes and outcomes

  • Subcutaneous immunotherapy (SCIT)
    • Traditional, weekly injections followed by monthly maintenance for several years; efficacy established across inhalant allergens and venom.
    • IgE-blocking activity in SCIT is predominantly carried by IgG4; nasal fluid blocking in SLIT is mainly IgA (IgA1/IgA2).
  • Sublingual immunotherapy (SLIT)
    • Direct mucosal exposure to allergen under the tongue; self-administration after a supervised first dose.
    • Systematic reviews/meta-analyses show efficacy for seasonal rhinitis (pre- and co-seasonal) and perennial rhinitis due to house dust mite (HDM).
    • Randomized trials with SLIT tablets show robust symptom improvement and reduced rescue medication use; long-term benefits persist for at least 2 years after stopping, especially for pollen (grass, ragweed, birch, Japanese cedar).
    • In HDM-induced perennial rhinitis, SLIT tablets are effective but effect sizes are smaller (approx. 17–20% improvement over placebo).
    • In HDM-induced asthma, SLIT tablet therapy improves outcomes and can reduce steroid requirements.
  • Oral immunotherapy (OIT) for foods
    • Peanut OIT has produced desensitization but long-term tolerance remains less robust and is associated with higher rates of adverse effects.
    • PALISADE trial established efficacy of a commercially available peanut OIT product (AR101) for desensitization in peanut allergy; however, sustained unresponsiveness after discontinuation varies.
    • Prolonged high-dose OIT (e.g., 4,000 mg daily) can achieve desensitization but sustained unresponsiveness after cessation occurs in a minority of participants (e.g., ~13% in one trial; ~21% in another).
    • Early-life peanut introduction and/or OIT in infancy shows potential for prevention of peanut allergy, particularly when baseline peanut-specific IgE is low and basophil reactivity is reduced.
  • Epicutaneous immunotherapy (EPIT)
    • Peanut patches deliver allergen via the skin and can desensitize some children with reduced systemic side effects; may lower risk of systemic anaphylaxis but overall efficacy is modest.
  • Intralymphatic immunotherapy
    • Direct injection of allergen into lymph nodes to enhance T cell exposure; early trials show modest clinical benefit with several injections, but evidence is limited.
  • Venom immunotherapy
    • Subcutaneous venom immunotherapy (VIT) is highly effective at preventing anaphylaxis from insect stings; rapid desensitization with accelerated protocols is possible via short-term “rush” or “ultra-rush” regimens.
    • Early desensitization involves rapid suppression of basophil activation, mediated by histamine H2 receptors (HR2) and shifts in histamine receptor expression that favor IL-10–producing Tregs and related regulatory networks.
    • A distinct regulatory B cell subset (Breg) secreting IL-10 and IgG4 supports long-term tolerance; unlike inhalant immunotherapy, venom immunotherapy shows persistent suppression of allergen-specific IgE even after discontinuation, with less persistent IgG-blocking activity.

Mechanisms of oral immunotherapy for peanut allergy in detail

  • TH2 cell dynamics in peanut OIT
    • Desensitization correlates with a reduction in TH2A cells and effector memory TH2 cells, including CRTH2+CD161+CD27– phenotype.
    • Earlier studies showed transient IL-10 secretion and Treg cell markers (e.g., CD25+ FOXP3+), but later analyses suggest the declines in TH2A cells are central and may occur with limited peripheral Treg expansion.
  • Basophil and IgE responses during OIT
    • Early decrease in basophil activation (lower CD203c surface expression) coincides with an increase in peanut-specific IgG4 relative to IgE and a reduction in IgE binding to FcεRI, contributing to desensitization.
  • Long-term outcomes
    • Prolonged high-dose exposure yields desensitization, but long-term tolerance (sustained unresponsiveness) is not consistently achieved for peanut, unlike some inhalant regimens.
  • Influences on memory and epitope recognition
    • Conformational vs linear epitopes, multivalent IgE responses, and TH2A cell dynamics may determine durability of tolerance after cessation.
  • Implications for prevention
    • Very early peanut introduction in infancy with low peanut-specific IgE may support sustained unresponsiveness, suggesting a potential preventive strategy rather than lifelong daily dosing.

Allergen immunotherapy for venom: immune changes and tolerance

  • Immunotherapy with purified venom allergens enables precise mechanistic study without confounding endotoxins.
  • Rapid desensitization involves early basophil silencing through FcεRI and HR2 signaling; shifts in histamine receptor balance (HR2/HR1) promote IL-10–producing Tregs.
  • PLA2-specific regulatory B cells develop with VIT, producing IL-10 and IgG4; maintaining allergen-specific IgG4 and IgE-blocking activity correlates with clinical protection.
  • During venom immunotherapy, long-term tolerance shows persistent suppression of allergen-specific IgE even after treatment ends, suggesting a distinct mechanism from inhalant allergen immunotherapy that relies more on persistent IgG/IgA blocking activity.
  • Overall, venom immunotherapy highlights the importance of rapid basophil desensitization, receptor expression patterns, and Breg cell involvement in achieving durable tolerance.

Current and novel approaches: safety, standardization, and future directions

  • Safety and standardization
    • SCIT requires specialist supervision due to risk of systemic reactions including anaphylaxis.
    • In the USA, extracts are typically formulated with 50% glycerin; in Europe, alum-precipitated extracts slow allergen release to reduce immediate side effects.
    • WHO guidelines (1998) highlighted safety concerns and the need for standardized extracts; later position papers endorsed SLIT as a safer alternative.
  • Modified allergens and allergoids
    • Chemical modification (glutaraldehyde/formaldehyde) yields allergoids with altered structure and reduced allergenicity; efficacy appears modest and may not significantly reduce adverse events due to retention of some IgE epitopes or new epitopes.
    • Shorter peptide fragments or hypoallergenic variants can induce protective IgG without strong IgE activation but have not consistently outperformed conventional standardized extracts.
  • Sublingual immunotherapy (SLIT) details
    • SLIT aims to access mucosal dendritic cells directly; daily administration (liquid or tablet) under the tongue, with first dose in clinic.
    • Systematic reviews support efficacy for seasonal rhinitis (pre/co-seasonal) and perennial rhinitis due to HDM; three well-powered adult and pediatric trials demonstrate long-term benefit after treatment cessation (at least 2 years).
    • HDM SLIT tablets show efficacy in perennial HDM-induced rhinitis/asthma; effect sizes are roughly in the range of 17–20% improvement vs placebo, possibly lower than pollen SLIT due to participant selection.
  • Molecular allergology
    • Cloning and recombinant production of major/minor allergens enable precise molecular diagnosis, better matching of immunotherapy to an individual's IgE profile, and monitoring of IgE/IgG responses during therapy.
    • Recombinant allergen mixtures and hypoallergenic variants have entered trials; so far they have not shown clear superiority to standard extracts in efficacy or safety, though they may allow personalized vaccines in the future.
  • DNA-based vaccines and CpG adjuvants
    • DNA vaccines in animal models favor TH1/Treg responses and reduce TH2 skewing, but human safety concerns (genome integration, anti-DNA antibodies, prolonged allergen persistence) require careful assessment.
    • Approaches combining allergen with CpG motifs to activate TLR9 (e.g., Amb a 1 linked to CpG ODN; HDM with G10 CpG ODN in virus-like particles) showed phase 2 signals but mixed results in later trials; some strategies were discontinued.
    • mRNA-based vaccines have shown success for SARS-CoV-2 and are of interest for allergic diseases, with preclinical data suggesting potential to elicit TH1/Treg responses and suppress inflammation.
  • Targeted cellular approaches
    • T cell–focused strategies use short peptides from major allergens to drive protective T cell responses with limited B cell (IgE) activation; however, field results have been mixed, and some phase 3 trials failed.
    • Cat and bee venom peptide-based therapies demonstrated some clinical benefit but did not consistently translate into durable protection; risk of late-phase reactions remains a concern.
  • B cell–focused and passive immunotherapy
    • Passive immunotherapy using anti–Fel d 1 monoclonal antibodies can block IgE epitopes and inhibit nasal challenge responses; effects persisted for weeks to months in some trials.
    • Similar monoclonal antibody strategies targeting Bet v 1 have shown short-term inhibition of nasal challenge responses.
    • Active immunization with recombinant allergen-derived B cell peptides (e.g., BM32) can boost allergen-specific IgG1/IgG4 with minimal changes in IgE, showing potential for safety and efficacy, though phase 3 results are awaited.
  • Allergen combination strategies
    • Combining allergen extracts with monoclonal antibodies targeting the TH2 pathway (e.g., anti-IgE/omalizumab, anti-IL-4/IL-4R, anti-TSLP, anti-IL-33) or Toll-like receptor (TLR) agonists to skew toward TH1/decrease TH2 is under investigation.
    • TLR4 agonists with grass pollen allergoids showed modest efficacy; anti-IgE co-therapy reduces systemic side effects but did not improve long-term tolerance.
    • Combining allergen with anti-IL-4 (or anti-IL-4R) has shown reductions in TH2 cells but not necessarily durable suppression of late-phase responses; trials continue with inhalant and peanut indications.
  • Practical considerations for future therapy
    • The goal is to achieve safe, effective, convenient regimens with durable long-term tolerance, potentially over shorter courses or via route-specific combinations that leverage complementary mechanisms.
    • A major objective is to enable preventive strategies (primary prevention in infancy) and to reduce steroid burden and asthma progression in HDM-triggered disease via sublingual tablets.
    • Molecular and passive immunotherapy approaches may pave the way for personalized vaccines tailored to an individual's IgE sensitization pattern and immune response characteristics.

Perspectives on long-term tolerance, prevention, and early intervention

  • For inhalant allergies, current best approach to achieve durable tolerance remains standard allergen immunotherapy with whole allergen extracts given via SCIT or SLIT for about three years; this regimen has demonstrated long-term clinical efficacy and persistence of protective antibodies after discontinuation.
  • The IgE-inhibitory activity profile differs by route: SCIT tends to rely on IgG4-mediated blocking antibodies, while SLIT relies more on IgA (local and systemic) blocking antibodies.
  • Subcutaneous and sublingual routes are mechanistically distinct, suggesting potential complementary use in resistant cases to maximize tolerance while maintaining safety.
  • Immunotherapy continues to hold promise for asthma prevention and reducing asthma symptoms, with data suggesting secondary preventive effects in children treated for seasonal rhinitis.
  • Primary prevention in infants (HDM-related and peanut strategies) is an active area of investigation; early introduction of potentially allergenic foods (e.g., peanut) may reduce the risk of developing clinical allergy.
  • For peanut allergy, very early intervention and combination strategies (including possible anti-TSLP or anti-IL-33) may promote more durable tolerance, but safety, efficacy, and long-term outcomes require confirmation in ongoing trials.
  • Epicutaneous peanut immunotherapy may offer a safer approach with reduced systemic exposure, potentially serving as a preventive or risk-reduction strategy rather than a route to sustained tolerance.
  • In summary, the future of allergen immunotherapy lies in: (i) combination strategies to improve efficacy and safety; (ii) molecular allergology enabling precision diagnosis and personalized vaccines; (iii) targeted B cell and T cell approaches; (iv) preventive strategies starting in infancy; and (v) tailoring regimens to individual risk profiles and IgE responses to maximize long-term tolerance while minimizing adverse events.

Practical takeaways for exam preparation

  • Immunotherapy aims to convert allergic disease into a tolerable, disease-modifying condition via induction of regulatory cells and IgG/IgA blocking antibodies that reduce TH2 signaling and IgE-mediated effector functions.
  • Three core mechanisms underlie long-term tolerance: (a) regulatory cell induction (Treg/Breg) with IL-10, TGF-β, IL-35; (b) immune deviation from TH2 toward TH1/TH0; (c) expansion of IgG/IgA blocking antibodies that prevent IgE–allergen interactions and IgE-facilitated antigen presentation.
  • The mainstay regimens for inhalant allergies remain three years of standard allergen immunotherapy via SCIT or SLIT to achieve durable tolerance; safety and route-specific effects vary by modality.
  • Peanut OIT achieves desensitization but sustained unresponsiveness is less consistently achieved in older children and adults; early-life intervention and combination strategies may improve durability.
  • Venom immunotherapy illustrates rapid basophil silencing and IgG4/Breg involvement; long-term tolerance may persist with IgE suppression even after discontinuation.
  • Future directions emphasize personalized vaccines, recombinant allergens, hypoallergenic variants, and combination therapies with mAbs or TLR agonists to broaden applicability and durability of tolerance.

References to figures and supplementary materials mentioned in the source

  • Fig. 1: Key milestones in allergen immunotherapy (historical timeline)
  • Fig. 2: Mechanisms of allergic inflammation and immunotherapy-induced tolerance (cellular interactions among DCs, TH2, Treg/Breg, IgG/IgA, and effector cells)
  • Fig. 3: Current and novel approaches to immunotherapy (combination strategies, monoclonal antibodies, recombinant allergens, peptides, and CpG/TLR adjuvants)
  • Supplementary Table S1: Randomized controlled trials confirming long-term efficacy after discontinuation (for inhalants)

Notes on terminology used in the source

  • SCIT: Subcutaneous immunotherapy
  • SLIT: Sublingual immunotherapy
  • OIT: Oral immunotherapy
  • EPIT: Epicutaneous immunotherapy
  • TH2: T helper 2 cells; TH2A: a subset of TH2 cells with a distinctive marker profile
  • Treg: Regulatory T cells; Breg: Regulatory B cells
  • IgG/IgA: Blocking antibodies that compete with IgE for allergen binding
  • FcεRI/FcεRII: High- and low-affinity IgE receptors on mast cells, basophils, and B cells
  • ILC2: Group 2 innate lymphoid cells; IL-33/TSLP/IL-25 regulate TH2 responses
  • MATA MPL: Allergen modification approach using monophosphoryl lipid A (TLR4 agonist) coupled with allergoids
  • BM32: Recombinant B cell epitope–containing peptides fused to a carrier protein (Pre-S) for selective IgG induction