Sublingual allergen immunotherapy for respiratory allergies what is new

June 23, 2015


Disclosure

Moises A Calderon has received lecture fees from ALK, Allergopharma, Merck and Stallergenes and served as a consultant to ALK, Hal Allergy, Merck and Stallergenes. No funding was received for the publication of this article.


Keywords

Sublingual immunotherapy, allergic rhinitis, allergic asthma, respiratory allergy


Correspondence

Moises A Calderon, Imperial College London, National Heart and Lung Institute, Royal Brompton Hospital NHS, Dovehouse Highway, London SW3 6LY, UK. E: [email protected]

In the tardy 1980s, sublingual allergen immunotherapy (SLIT) was proposed as an ‘alternative’ to subcutaneous allergen immunotherapy (SCIT).1,2 The main purpose was to reduce systemic reactions and the risk of anaphylaxis, which were frequently associated with SCIT and also to increase the number of patients receiving allergen immunotherapy by facilitating its regular use at home.

Over the years, through well-designed, well-powered studies, the scientific community has increased the levels of evidence of SLIT regarding its efficacy and safety.

Nowadays, the use of SLIT has been included in international guidelines for the treatment of allergic rhinitis with or without conjunctivitis.3

SLIT can be istered as drops or tablets for respiratory allergies due to grass, tree and ragweed pollens, and home dust mites (HDM). Some SLIT products are commercialised and routinely used in some European countries. More recently, the US Food and Drug istration (FDA) gave the approval for three SLIT products (two for grasses; one for ragweed).

The clinical efficacy of SLIT is well documented in diverse double blind, placebo-controlled, randomised clinical trials (DB PC RCTs) and metaanalyses.

4 SLIT significantly reduces nasal and ocular symptoms scores, reduces the use of relief medication and improves quality of life in both adults and children with pollen respiratory allergy.

Large and complicated clinical development programmes on SLIT own been conducted in Europe and the US. Well-powered, well-designed multinational DB PC RCTs using almost comparable clinical outcomes and well-standardised sublingual products own demonstrated sustained clinical efficacy of the SLIT tablets compared with placebo for pollen respiratory allergy. These studies own also indicated a disease modification 2 years after completion of 3 years of treatment with SLITtablets for grass allergy.5,6

More recently, the significant clinical effect of SLIT tablets for HDM respiratory allergy own been demonstrated in adults with perennial HDM rhinitis and asthma due to HDM.

Nasal and ocular symptoms and the risk of asthma exacerbations own been reduced after treatment with SLIT-tablets for HDM.

SLIT’s safety profile is extremely good.7 Symptoms are mainly localised to the oral mucosa, such as itching/tingling of the lips or mouth, mild local swelling of lips, sublingual area or tongue. These symptoms are mild in severity and are self-limiting.5–7 To re-assure the patient of the safety profile and to inform about the expected local symptoms of SLIT, it is always recommended that the first dose should be taken at the doctors’ office. SLIT is prescribed to be self-istrated by the patients in their homes.

Systemic reactions due to SLIT are rare.

Extremely few ‘so-called’ anaphylactic cases own been reported globally. There own been no fatalities related to SLIT.

Good adherence to SLIT is critical for its success, at least three to four visits per year should be scheduled to assess SLIT’s adherence and clinical response.

SLIT drops or tablets should be placed under the tongue, allowing the allergen to be in contact for at least 2 minutes with the oral mucosa. The proposed mechanism is that the allergens are captured by tolerogenic dendritic cells and processed as little peptides.

SLIT takes advantage of this tolerogenic environment of the oral mucosa to promote tolerance to the allergen.8 Following the uptake of allergen during SLIT, there is differentiation of T helper cell type 1 (Th1) and the induction of interleukin (IL)-10-producing regulatory T cells. Following SLIT, allergic disease-promoting Th2 responses shift to a Th1 inflammatory response, and IL-10 and transforming growth factor (TGF)-β production by regulatory T cells. SLIT also promotes the synthesis of allergen-specific immunoglobulin (Ig)-G and IgA antibodies that block allergen-IgE complicated formation and binding to inflammatory cells, thus encouraging an anti-inflammatory environment.

An early increase and a extremely tardy decrease in specific IgE levels are observed after SLIT. IgG4 levels show a relatively early increase that is dose dependent. A significant decrease in the allergen-specific IgE/IgG4 ratio occurs after several months.8

The potential preventive effect of asthma development in children with allergic rhinitis using SLIT grass tablet is currently being evaluated in a large DB PC RCT, the Grass Asthma Prevention trial (GAP). Children are receiving 3 consecutive years of SLIT-tablet treatment followed by 2 years observation after cessation of treatment. If the results of this study are positive, then we will own a significant change in the way children with grass allergic rhino-conjunctivitis are treated in the future.

The new SLIT products should be considered as a ‘new therapeutic class’ for the management of these allergic conditions. Emphasis should be put on the selection of patients. SLIT should only be prescribed to individuals with proven clinical respiratory symptoms on exposure to the culprit allergen, confirmed by positive skin test or in vitro testing for the allergen-specific IgE antibodies. The decision to use SLIT depends on practical considerations, experience of the prescribing physician with the respective treatment form, cost, convenience and patient’s preference.

Considering every these recent advances in SLIT, which are supported by strong evidence-based medicine data on clinical efficacy, safety and with the better understanding of the immunological mechanisms involved, we are entering a new era in the treatment of respiratory allergic diseases.

Immunotherapy is considered to be the only curative treatment for allergic diseases such as pollinosis, perennial rhinitis, asthma, and food allergy.

The sublingual route is widely applied for immunotherapy for allergy, instead of the conventional istration by subcutaneous route. A recent meta-analysis of sublingual immunotherapy (SLIT) has shown that this approach is safe, has positive clinical effects, and provides prolonged therapeutic effects after discontinuation of treatment. However, the mechanism of SLIT and associated biomarkers are not fully understood. Biomarkers that change after or during SLIT own been reported and may be useful for response monitoring or as prognostic indicators for SLIT. In this review, we focus on the safety, therapeutic effects, including prolonged effects after treatment, and new methods of SLIT.

We also discuss response monitoring and prognostic biomarkers for SLIT. Finally, we discuss immunological mechanisms of SLIT with a focus on oral dendritic cells and facilitated antigen presentation.

Mechanisms of SLIT

Treg cells frolic an significant role in suppression of Th2 responses and inflammatory cells [4, 71]. However, the cells that induce Treg cells after sublingual istration of allergens and the mechanism of induction remain unclear.

DCs that preferentially induce Treg cells are thought to be located in the sublingual mucosa. In a mouse study, three types of DCs with diverse surface markers were identified within lingual and buccal tissue: CD207+ Langerhans cells in the mucosa, CD11b+CD11c and CD11b+CD11c+ myeloid DCs at the mucosal/submucosal interface, and B220+120G8+ plasmacytoid DCs [72]. Oral CD11b+CD11c DCs induced IFN-γ production by T cells, and oral CD11b+CD11c+ DCs and B220+120G8+ DCs induced IFN-γ and IL10 production by T cells in an antigen-specific manner.

These oral DCs may preferentially skew development to antigen specific Th1 or Treg. The function of CD207+ Langerhans cells could not be sure because of limited cell numbers. In humans, oral mucosal Langerhans cells (oLCs) that constitutively express FcεRI on the surface own been found in atopic and nonatopic subjects [73]. Expression levels of FcεRI were found to be significantly correlated with serum IgE levels in atopic subjects. oLCs also expressed significantly higher amounts of major histocompatibility complicated (MHC) I and II, CD40, CD80, and CD86 compared to skin Langerhans cells [73].

Toll-like receptor 4-ligation of oLCs has also been shown to induce production of IL10, TGF-β, IL2, IFN-γ, and Foxp3 [74], and oLCs might capture allergens within sublingual mucosa and present them to T cells to develop antigen-specific Treg cells [75, 76]. Further studies are needed to determine the importance of oral DCs and oLCs in the therapeutic mechanisms of SLIT.

Induction of IgG and IgG4 as blocking antibodies in SLIT is still under debate [77, 78]. IgE enhances uptake and presentation of invading antigens by APCs via CD23, a process known as facilitated antigen presentation (FAP), and transcytosis by human airway epithelial cells in a CD23-dependent manner [79, 80].

The immune complicated of IgE with antigen binds to CD23, and this binding leads to enhance antigen presentation by APCs to T cells [79]. There is increasing evidence to show that SLIT inhibits FAP by preventing binding of IgE with antigen or CD23 [81]. Decreased FAP after immunotherapy is correlated with T-cell activation in vitro and antigen-specific IgG titer, and FAP activity tends to correlate with IgE/IgG4 ratio and symptom score [82–84].

This inhibition of FAP leads to decrease antigen-specific proliferation and IL4, IL5, IL10, and IFN-γ production from T cells [85]. The inhibition persists over 2 years after discontinuation of 2-year immunotherapy although specific IgG and IgG4 levels decreased to preimmunotherapy levels [86]. Other factors may also be involved in the mechanism of FAP by inhibiting CD23 and IgE binding.

Unmet Problems in SLIT

Compliance with self-istration at home may be an significant factor in the therapeutic effect of SLIT. Compliance with SLIT is likely to be similar to that for other self-istered drug treatments for allergy [11], and education on the SLIT protocol is needed for excellent compliance [39, 40].

Checking the compliance of each patient based on the quantity of remaining vials or tablets may also be significant for evaluating the efficacy of SLIT in clinical trials [34]. A device that reminds patients about intake of allergens may be useful to achieve excellent compliance in endless term istration and to improve the efficacy of SLIT [41]. Delivery as a tablet or solid form may be better than an aqueous solution using an atomizer or dispenser to achieve excellent compliance and to hold allergens stably under the tongue because human error or bad conditions of a nozzle may lead to istration of an inaccurate quantity of liquid drops.

Such mistakes may also increase the risk of adverse reactions [17].

Bystander therapeutic effects of SLIT using allergens from a single source with polysensitized patients are uncertain. Inferior therapeutic effects for a polysensitized population own been reported compared with a monosensitized population [42]. Recent findings own shown that the use of both single and mixed allergen extracts improved mean QOL scores, increased threshold of a titrated nasal challenge, and decreased skin prick tests reactivity in polysensitized patients [43–45]. The efficacy of SLIT for polysensitized patients has also been found to be comparable with that for monosensitized patients [28].

Furthermore, SLIT for monosensitized (rhinitis only) and polysensitized (rhinitis and asthma) patients prevented or reduced additional sensitization compared with drug treatment [46, 47]. These preventive effects of SLIT were clearer for monosensitized patients. In contrast, SLIT for birch pollinosis was not effective against an already established apple allergy [48]. Mal d 1, a major allergen in apple, has 64% identity in amino acid sequence with Bet v 1, a major allergen in birch, and these allergens are cross-reactive in IgE-binding and T-cell activation.

Bystander effects of SLIT using allergens from a single source for patients with other established allergies may depend on the allergens used for immunotherapy and the degree of sensitization to the allergy. Further clinical trials and meta-analyses are needed to assess the bystander and prophylactic effects of SLIT.

In 2010, the World Allergy Organization defined a systemic reaction grading system for scoring of adverse reactions by SCIT to enable comparison of the severity of adverse events among clinical trials [49]. A similar approach to evaluation of clinical effects and adverse events in SLIT is needed to compare the clinical effects and therapeutic efficacy among studies that differ in allergen, dose, and method and protocol of istration.

This will permit improved meta-analyses. Currently, it is hard to optimize the SLIT protocol using results from multiple clinical trials that used diverse methods for evaluation of therapeutic effects, such as cumulative or average scores for symptoms and medication, QOL, VAS, local symptoms, and days with mild or severe symptoms over periods of days, months, seasons, and years [18, 50, 51]. It will be hard to score the severity of allergic symptoms using the same grading system because both the pattern and main organ in which symptoms appear may differ among seasonal or perennial allergies in various areas.

However, a scoring or grading system for use in scientific reports is needed as a minimum requirement to permit improved understanding by readers.

Safety and Therapeutic Effects of SLIT

Increasing numbers of clinical trials and meta-analyses own shown positive clinical effects and safety of SLIT. However, several case reports own also described anaphylactic shock or severe fatal reactions induced by sublingual istration of allergens [12–17]. In the reports, four patients experienced severe side effects with SCIT and discontinued the treatment prior to SLIT [15, 16].

Patients who own experienced severe side effects in SCIT may be at risk for a severe fatal reaction in SLIT. To prevent an allergen overdose, a tablet or solid form for sublingual istration may be better than the use of an atomizer or dispenser for istration of liquid allergens, especially for young children. Despite the few case reports of severe fatal events, life-threatening severe fatal reactions own not been found in clinical trials [18].

Therefore, SLIT is considered to be a safe treatment in which reactions such as anaphylaxis can be avoided by using correct clinical protocols.

It takes a few weeks to six months to reach a maintenance dose using SCIT with a previous updosing phase to reduce the risk of side effects [19]. In some studies, a build-up phase is used for SLIT before istering the maintenance dose of allergens. A comparison of the clinical effects and safety among four diverse SLIT regimes for grass pollen allergy using a mixture of extracts of five grass pollens (Anthoxanthum odoratum, Dactylis glomerata, Lolium parenne, Phleum pratense, and Poa pratensis) concluded that a short build-up phase reduces the incidence of adverse events in istration of high-dose SLIT [20].

In this phase I study, the numbers of adverse events were compared among four athletic groups with a build-up phase repeating each concentration from 100 to 500 IR for 2 days (), a single daily build-up phase of 100 to 500 IR (), and no build-up phase for doses of 300 IR () or 500 IR (). Every groups showed mild and moderate adverse events, but only the group istered 500 IR without a build-up phase showed severe local adverse events (swelling of throat). A placebo group () showed only mild adverse events.

Another study compared the safety and efficacy among 3 SLIT groups with a build-up phase of 500 to 1,000 AU for 4 days, 300 to 1,200 AU for 4 days, and no build-up phase for a dose of 1,000 AU, using orosoluble tablets of a monomeric carbamylated allergoid [21].

Sublingual allergen immunotherapy for respiratory allergies what is new

Safety and efficacy were comparable among these groups, based on evaluation using a Visual Analog Scale (VAS), the Symptom Medication Score (SMS), and a nasal provocation test. An ultrarush schedule for SLIT has also been shown to be safe during the updosing phase, but severe systemic and local adverse events may happen in the maintenance phase [22, 23]. In contrast, urticaria has been reported to happen in an ultrarush protocol [24]. The safety of this protocol may depend on the type and biological function of the causal allergens. It has also been suggested that the build-up phase for SLIT can be omitted or shortened compared to that for SCIT [25].

A recent meta-analysis found positive clinical effects of SLIT based on the results from 49 papers describing randomized, double-blind, and placebo-controlled (DBPC) trials [18].

The standardized mean differences (SMDs) for the symptom and medication scores were −0.49 () and −0.32 (), respectively, in favor of athletic treatment (active; , placebo; ). A meta-analysis of SLIT for grass pollinosis gave SMDs for the symptom (active; , placebo; ) and medication (active; , placebo; ) scores of −0.32 () and −0.33 (), respectively, in favor of athletic treatment compared with placebo [26]. Both meta-analyses showed positive therapeutic effects of SLIT, especially for seasonal rhinitis, and these effects are comparable with those of SCIT [18, 27–29]. It has also been suggested that immunotherapy with SLIT and SCIT in combination may be beneficial [30].

In this study, 60 children with mild or moderate asthma or rhinitis who were monosensitized to home dust mite received injection of a mixture of Dermatophagoides allergens in a glycerinated solution. SCIT was used in a build-up phase for 16 weeks and was followed by SLIT three times a week as the maintenance phase. The clinical effects of SLIT were less than those of SCIT after 4 and 18 months and comparable after 12 months of treatment, based on the required dose of inhaled corticosteroids and the number of asthma attacks per year. SCIT and combination therapy of SLIT and SCIT significantly decreased the dose of inhaled corticosteroids and the number of asthma attacks at 4, 12, and 18 months and significantly improved the VAS for rhinitis.

An advantage of SLIT is that sublingual self-istration can be performed at home during the maintenance phase, avoiding the need for patients to go to clinic for subcutaneous injection of allergens.

There is also increasing evidence for clinical effects after an extended period of SLIT and for prolonged clinical effects after treatment [31]. SLIT in 24 children with respiratory symptoms due to monosensitization to home dust mite showed a lack of positive clinical effects in the first year, but significant amelioration of rhinitis and asthma in the second and third years compared to the first year of treatment [32].

A study of 137 patients allergic to home dust mite also showed clinical effects in 2-year and 3-year SLIT and prolonged therapeutic effects at 4 and 3 years, respectively, after these treatments [33]. Scores for nasal airway resistance, secretion, symptoms, and skin prick test were significantly reduced at the finish of the first year, and the nasal secretion score was significantly reduced at the finish of the second year of treatment. Two-year SLIT significantly attenuated nasal airway resistance, secretion, sneezing, symptoms, and skin prick scores at 1 and 4 years after treatment compared with the respective scores at the start of treatment although every scores except for nasal airway resistance at 4 years after treatment were slightly, but significantly, higher than those at the finish of treatment.

Three-year SLIT significantly attenuated these scores at the finish of treatment, and entire score of nasal airway resistance, secretion, and sneezing, score for the nasal airway resistance, and symptom score at 3 years after treatment were similar to or lower than those at the finish of treatment.

Carry-over effects of SLIT are supported by other studies. DBPC trials of 3-year SLIT for grass pollen allergy showed significantly decreased scores for symptom and the rhinoconjunctivitis quality-of-life questionnaire (RQLQ), and SMS and the medication score tended to decrease with athletic treatment compared with those for placebo at 1 year after SLIT [34, 35].

Our recent results also propose a 1-year prolongation of clinical effects after 2-year SLIT for Japanese cedar pollinosis [36]. Analysis of 88 participants (SLIT; , placebo; ) showed positive therapeutic effects in the second year of SLIT compared with placebo (reduction of SMS by 21%, ) and at 1 year after treatment (23%, ) (Figure 1). A recent phase III trial performed as a large-scale randomized, DBPC study using a 75,000 SQ-T/2,800 BAU tablet in 257 subjects allergic to grass pollen also has shown that 3-year SLIT significantly decreased the mean rhinoconjunctivitis symptom and medication scores at 1 year after treatment compared with placebo.

The results showed reductions of symptom scores of 31%, 36%, 29%, and 26% and reductions of medication scores of 38%, 45%, 40%, and 29% after 1, 2, and 3 years of treatment and after a follow-up year, respectively [37]. Long-lasting effects after 3-, 4-, and 5-year SLIT were evaluated in a 15-year prospective open controlled study in 59 patients with respiratory allergy for mite [38]. A decreased SMS of <50% of the baseline score (at the start of treatment) was found over the following 6 years after 3-year SLIT, and over 8 years after 4- and 5-year SLIT. The SMS after loss of the prolonged therapeutic effects increased to levels comparable with those in the control group.

Significant clinical effects were obtained in a second course of SLIT given after the initial effects had vanished.

Conclusions

One of the aims of immunotherapy is to induce tolerance against invading allergens. The therapeutic effects and efficacy of SLIT vary among allergies with diverse causal allergen sources. Achievement of a level of tolerance at which drugs are not required and symptoms are absent in the greatest numbers of patients requires further optimization of protocols and modification of SLIT or standardization of allergens as a SLIT vaccine.

Adjuvant SLIT and combination with other methods may assist to achieve more effective SLIT. The involvement of oral DC, oLCs, Treg, and FAP in the therapeutic mechanisms of SLIT has been proposed in numerous studies in humans and in mice (Figure 3). To determine the chain of mechanisms of SLIT, more studies are needed using human materials from clinical trials with large sample numbers. Understanding the precise mechanisms of SLIT should facilitate more effective immunotherapy for more patients with allergies.

Trials of Adjuvant Therapy with SLIT

Coistration of an adjuvant with allergens may achieve more efficient and effective SLIT.

Numerous studies in mouse models of asthma or rhinitis own shown increased effects of SLIT with adjuvant therapy. In most cases, the adjuvant is used to enhance development or activation of regulatory T cells (Treg) or increase adherence or permeability of allergens in sublingual mucosa to enhance uptake by antigen-presenting cells (APCs) such as mucosal dendritic cells (DC). Sublingual istration of an antigen conjugated with the nontoxic B subunit of cholera toxin to mice significantly induced antigen-specific Foxp3+CD4+ T cells in cervical lymph nodes and spleen and suppressed proliferation of cells from cervical lymph nodes after stimulation with antigen to a greater extent than that after treatment with the unmodified antigen.

The serum TGF-β level was also higher after istration of the modified antigen compared to the unmodified antigen [52]. Sublingual coistration of an antigen with either 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3/DEX) or Lactobacillus plantarum suppressed airway hyperresponsiveness (measured as PenH) compared with antigen alone, and coistration with VitD3/DEX significantly induced Foxp3+ cells in mice [53]. Another mouse study supported the adjuvant activity of lactic acid bacteria in enhancing the therapeutic effects of SLIT [54].

A study using polymerized carbohydrate as a mucoadhesive adjuvant showed superior reduction of established airway hyperresponsiveness (PenH) and lung inflammation compared to istration of antigen alone or phosphate-buffered saline [55]. In this study, IL5 and IL10 production from splenocytes was reduced after stimulation with antigen in mice-istered antigen with adjuvant compared with mice-istered PBS or antigen alone. The therapeutic effects of adjuvant SLIT are also under evaluation in humans.

In a Phase I/IIa study, coistration of grass allergens with a high dose of monophosphoryl lipid A, an agonist for toll-like receptor 4, significantly increased the rate of negative findings in a nasal challenge test at two weeks after completion of 8-week treatment [56]. Further large scale studies are needed to assess the efficacy of adjuvant SLIT in humans.

Recent Findings on Biomarkers for SLIT

Candidate biomarkers for response-monitoring or prognosis own been proposed and evaluated in numerous studies [4, 57, 58]. IL10 and Treg cells appear to be involved in the therapeutic mechanism of SLIT [59–61]. We reported upregulation of antigen-specific Treg cells (IL10+Foxp3+ cells) in CD25+CD4+ leukocytes from pre- to postpollen season as a response-monitoring biomarker for SLIT [36, 62].

Among patients treated with SLIT, entire QOL and QOL-symptom scores after 2 years of treatment significantly improved in a subgroup with increased Treg cells compared with the placebo group, whereas the scores in a subgroup with decreased Treg cells were similar to those in the placebo group (Figure 2(a)). We also proposed that the ratio of antigen-specific IgE to entire IgE (sIgE/tIgE) was a candidate as a prognostic biomarker for SLIT in a DBPC trial [36]. SMS in the SLIT group was correlated with the sIgE/tIgE ratio before treatment and was significantly improved in patients with a low sIgE/tIgE ratio compared to that in patients with a high sIgE/tIgE ratio (Figures 2(b) and 2(c)) [36].

The sIgE/tIgE ratio has been found to be significantly higher in responders than in nonresponders following 4-year immunotherapy [63]. In this study, responders to the immunotherapy (42 patients for SCIT and 103 patients for SLIT) showed higher grass- or mite-specific IgE/tIgE ratio than nonresponders (34 patients for SCIT and 100 patients for SLIT) evaluated with VAS score. In our trial, this ratio did not differ significantly between responders and nonresponders [36].

Further validation studies with a large sample size are needed before these biomarkers can be applied in the clinical management of SLIT.

Upregulation of regulatory molecules after SLIT has been reported [57, 64] and programmed cell death ligand 1 (PDL1), IL10, and IgG4 may serve as response-monitoring biomarkers for SLIT [65]. In this report, every patients who received preseasonal, seasonal, and prolonged SLIT had increased percentages of PDL1+ and IL10+PDL1+ cells among CD14+ and CD19+ cells after stimulation with antigen in pollen season, compared to a placebo group.

PDL1 is involved in induction and maintenance of Foxp3+CD4+ Treg cells in the presence of TGFβ in mouse [66, 67], and induction of PDL1 may frolic an significant role in induction of Treg cells by SLIT.

Apolipoprotein is involved in lipid metabolism and lipid transport, and apolipoprotein E has roles in lipid antigen presentation and inhibition of T-cell activation [68, 69]. Upregulation of apolipoprotein A-IV (ApoA-IV) in serum in pollinosis patients from pre- to postpollen season was found to be significantly greater with SLIT than with placebo and was inversely correlated with SMS and QOL scores in the SLIT group [70].

ApoA-IV also significantly reduces histamine release in vitro from basophils taken from patients [70], and ApoA-IV induced by SLIT may be involved in downregulation of local or peripheral inflammation during the pollen season.

Abbreviations

APC: antigen-presenting cells
DBPC: double-blind, placebo-controlled
DC: dendritic cells
SCIT: subcutaneous immunotherapy
SLIT: sublingual immunotherapy
SMD: standardized mean difference
SMS: symptom-medication score
Treg: regulatory T cells
QOL: quality-of-life
VAS: Visual Analog Scale.

(a)
(b)
(a)
(b)
(c)

Introduction

Allergic rhinitis is the most prevalent type I allergy, and pollen grains, mite, and mold are common causative allergens for seasonal or perennial rhinitis.

Antihistamines, leukotriene inhibitors, and nasal steroids are commonly used to treat respiratory allergy, but these drugs sometimes own side effects that induce impaired performance [1, 2]. Almost 100 years own passed since the first report of immunotherapy for pollinosis in 1911 [3]. Subsequently, the protocol for allergen-specific immunotherapy has improved to increase efficacy and safety through coinjection or conjugation of allergens with an immunomodulatory adjuvant, premedication with an antihistamine or anti-human IgE antibody, or use of a rush protocol to shorten the duration of the updosing phase [4–8].

The injection route for allergens has also been examined in trials of modified allergens to shorten the schedule and to increase the safety for immunotherapy [9, 10]. In the final few decades, sublingual istration has been recognized as a route of istration of allergens that is safer than subcutaneous injection, and there is increasing evidence that the therapeutic effects of sublingual immunotherapy (SLIT) are comparable with those of traditional subcutaneous immunotherapy (SCIT) [11].

In this review, we focus on the therapeutic effects of SLIT and the problems to be solved in future clinical studies.

We also discuss recent findings for prospective and response-monitoring biomarkers for SLIT, and we examine the cellular mechanisms of SLIT.

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Immune system response to a substance that most people tolerate well

For the medical journal of this title, see Allergy (journal).

Allergy
Hives are a common allergic symptom
Specialty Immunology
Symptoms Red eyes, itchy rash, runny nose, shortness of breath, swelling, sneezing[1]
Types Hay fever, food allergies, atopic dermatitis, allergic asthma, anaphylaxis[2]
Causes Genetic and environmental factors[3]
Diagnostic method Based on symptoms, skin prick test, blood test[4]
Differential diagnosis Food intolerances, food poisoning[5]
Prevention Early exposure to potential allergens[6]
Treatment Avoiding known allergens, medications, allergen immunotherapy[7]
Medication Steroids, antihistamines, epinephrine, mast cell stabilizers, antileukotrienes[7][8][9][10]
Frequency Common[11]

Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment.[12] These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis.[2] Symptoms may include red eyes, an itchy rash, sneezing, a runny nose, shortness of breath, or swelling.[1]Food intolerances and food poisoning are separate conditions.[4][5]

Common allergens include pollen and certain foods.[12] Metals and other substances may also cause problems.[12] Food, insect stings, and medications are common causes of severe reactions.[3] Their development is due to both genetic and environmental factors.[3] The underlying mechanism involves immunoglobulin E antibodies (IgE), part of the body’s immune system, binding to an allergen and then to a receptor on mast cells or basophils where it triggers the release of inflammatory chemicals such as histamine.[13] Diagnosis is typically based on a person’s medical history.[4] Further testing of the skin or blood may be useful in certain cases.[4] Positive tests, however, may not mean there is a significant allergy to the substance in question.[14]

Early exposure to potential allergens may be protective.[6] Treatments for allergies include avoiding known allergens and the use of medications such as steroids and antihistamines.[7] In severe reactions injectable adrenaline (epinephrine) is recommended.[8]Allergen immunotherapy, which gradually exposes people to larger and larger amounts of allergen, is useful for some types of allergies such as hay fever and reactions to insect bites.[7] Its use in food allergies is unclear.[7]

Allergies are common.[11] In the developed world, about 20% of people are affected by allergic rhinitis,[15] about 6% of people own at least one food allergy,[4][6] and about 20% own atopic dermatitis at some point in time.[16] Depending on the country about 1–18% of people own asthma.[17][18] Anaphylaxis occurs in between 0.05–2% of people.[19] Rates of numerous allergic diseases appear to be increasing.[8][20] The expression «allergy» was first used by Clemens von Pirquet in 1906.[3]

Immune system response to a substance that most people tolerate well

For the medical journal of this title, see Allergy (journal).

Allergy
Hives are a common allergic symptom
Specialty Immunology
Symptoms Red eyes, itchy rash, runny nose, shortness of breath, swelling, sneezing[1]
Types Hay fever, food allergies, atopic dermatitis, allergic asthma, anaphylaxis[2]
Causes Genetic and environmental factors[3]
Diagnostic method Based on symptoms, skin prick test, blood test[4]
Differential diagnosis Food intolerances, food poisoning[5]
Prevention Early exposure to potential allergens[6]
Treatment Avoiding known allergens, medications, allergen immunotherapy[7]
Medication Steroids, antihistamines, epinephrine, mast cell stabilizers, antileukotrienes[7][8][9][10]
Frequency Common[11]

Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment.[12] These diseases include hay fever, food allergies, atopic dermatitis, allergic asthma, and anaphylaxis.[2] Symptoms may include red eyes, an itchy rash, sneezing, a runny nose, shortness of breath, or swelling.[1]Food intolerances and food poisoning are separate conditions.[4][5]

Common allergens include pollen and certain foods.[12] Metals and other substances may also cause problems.[12] Food, insect stings, and medications are common causes of severe reactions.[3] Their development is due to both genetic and environmental factors.[3] The underlying mechanism involves immunoglobulin E antibodies (IgE), part of the body’s immune system, binding to an allergen and then to a receptor on mast cells or basophils where it triggers the release of inflammatory chemicals such as histamine.[13] Diagnosis is typically based on a person’s medical history.[4] Further testing of the skin or blood may be useful in certain cases.[4] Positive tests, however, may not mean there is a significant allergy to the substance in question.[14]

Early exposure to potential allergens may be protective.[6] Treatments for allergies include avoiding known allergens and the use of medications such as steroids and antihistamines.[7] In severe reactions injectable adrenaline (epinephrine) is recommended.[8]Allergen immunotherapy, which gradually exposes people to larger and larger amounts of allergen, is useful for some types of allergies such as hay fever and reactions to insect bites.[7] Its use in food allergies is unclear.[7]

Allergies are common.[11] In the developed world, about 20% of people are affected by allergic rhinitis,[15] about 6% of people own at least one food allergy,[4][6] and about 20% own atopic dermatitis at some point in time.[16] Depending on the country about 1–18% of people own asthma.[17][18] Anaphylaxis occurs in between 0.05–2% of people.[19] Rates of numerous allergic diseases appear to be increasing.[8][20] The expression «allergy» was first used by Clemens von Pirquet in 1906.[3]


Accepted

2015-08-17T00:00:00


Open Access

This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.



Sublingual immunotherapy (SLIT) – indications, mechanism, and efficacy Position paper prepared by the Section of Immunotherapy, Polish Society of Allergy

Ann Agric Environ Med. 2016;23(1):44–53

SLIT (sublingual immunotherapy) induces allergen-specific immune tolerance by sublingual istration of a gradually increasing dose of an allergen. The mechanism of SLIT is comparable to those during SCIT (subcutaneous immunotherapy), with the exception of local oral dendritic cells, pre-programmed to elicit tolerance.

In the SLIT dose, to achieve the same efficacy as in SCIT, it should be 50–100 times higher with better safety profile. The highest quality evidence supporting the efficacy of SLIT lasting 1 – 3 years has been provided by the large scale double-blind, placebo-controlled (DBPC) trials for grass pollen extracts, both in children and adults with allergic rhinitis. Current indications for SLIT are allergic rhinitis (and conjunctivitis) in both children and adults sensitized to pollen allergens (trees, grass, Parietaria), home dust mites (Dermatophagoides pteronyssinus, Dermatophagoides farinae), cat fur, as well as mild to moderate controlled atopic asthma in children sensitized to home dust mites.

There are positive findings for both asthma and new sensitization prevention. Severe adverse events, including anaphylaxis, are extremely rare, and no fatalities own been reported. Local adverse reactions develop in up to 70 – 80% of patients. Risk factors for SLIT adverse events own not been clearly identified. Risk factors of non-adherence to treatment might be dependent on the patient, disease treatment, physician-patient relationship, and variables in the health care system organization.

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Abstract

Sublingual allergen immunotherapy (SLIT) is a new alternative for the treatment of respiratory allergy. Strong evidence-based medicine data on clinical efficacy and safety about SLIT support the new standardised products register in Europe and the US. SLIT-tablets significantly reduce nasal and ocular symptoms scores, reduce the use of relief medication and improves quality of life in both adults and children with pollen respiratory allergy.

New data support its efficacy and safety for home dust mites (HDM) respiratory allergy.


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