Specific immunotherapy, one century later

Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: Looking at the published evidence

IntroductionThere is a need to evaluate the safety and efficacy of intralymphatic immunotherapy (ILIT) for inducing tolerance in patients with allergic rhinitis.MethodsThirty‐seven patients with seasonal allergic symptoms to birch and grass pollen and skin prick test >3 mm and/or IgE to birch and timothy >0.35 kU/L were randomized to either ILIT, with three doses of 0.1 mL of birch pollen and 5‐grass pollen allergen extracts on aluminium hydroxide (10,000 SQ‐U/ml; ALK‐Abelló) or placebo using ultrasound‐guided intralymphatic injections at monthly intervals. Daily combined symptom medical score and rhinoconjunctivitis total symptom score were recorded during the peak pollen seasons the year before and after treatment. Rhinoconjunctivitis total symptom score, medication score and rhinoconjunctivitis quality of life questionnaire were recorded annually starting 2 years after treatment. Circulating proportions of T helper cell subsets and allergen‐induced cytokine and chemokine production were analysed using flow cytometry and ELISA.ResultsThere were no differences between the groups related to daily combined symptom medical score the year before and after treatment. Two years after ILIT (after unblinding), the actively treated group reported significantly fewer symptoms, lower medication use and improved quality of life than did the placebo group. After the pollen seasons the year after ILIT, T regulatory cell frequencies and grass‐induced IFN‐γ levels increased only in the actively treated group.ConclusionIn this randomized controlled trial, ILIT with birch and grass pollen extract was safe and accompanied by immunological changes. Further studies are required to confirm or refute the efficacy of the treatment.

Allergen Specific Immunotherapy (SIT) for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2), which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for changes in the long-term prognosis of respiratory allergy. SIT should not only be recognised as first-line therapeutic treatment for allergic rhinoconjunctivitis but also as secondary preventive treatment for respiratory allergic diseases.

Intralymphatic allergen-specific immunotherapy: An effective and safe alternative treatment route for pollen-induced allergic rhinitis

Allergen-specific subcutaneous (SCIT) as well as sublingual (SLIT) immunotherapy both confer long-term protection against the highly prevalent IgE-mediated allergies, such as allergic rhino-conjunctivitis and asthma. Since both SCIT and SLIT are both very laborious and time-consuming treatments, we and others have investigated whether the immunotherapy could be enhanced by so-called intralymphatic immunotherapy (ILIT), which aims at improving treatment efficacy and safety and to reduce treatment duration, thereby making allergen immunotherapy (AIT) more patient friendly. In the original studies made by us (1, 2) and by Cardell et al (3), ILIT was administered three times with four week intervals. In 2013, Witten et al. questioned the efficacy of ILIT with grass pollen, based on the results of a clinical study of their in 38 adult hay-fever patients (4). While promising immunological changes such as increased IgG4 and Treg responses were observed, they concluded that the clinical outcome was at odds with that measured by us in 165 hay fever and 20 cat-dander allergic patients as well as in Cardell's study with 28 hay-fever patients. This article is protected by copyright. All rights reserved.

In a previous controlled study we demonstrated that preseasonal grass pollen immunotherapy for three years was effective in children. In the current study we examined the same group of patients to see if there is still a benefit six years after discontinuation of treatment. Thirteen of 14 patients with previous specific immunotherapy (SIT) and 10 out of 14 patients of the control group were prospectively followed during the grass pollen season. Outcome measures were seasonal symptom scores for eyes, nose and chest, the use of symptomatic medication and visual analog scale. Objective measures included skin prick test reactivity to seasonal and perennial allergens and conjunctival provocation testing. During the 13 week observation time scores for overall hayfever symptoms (P < 0.004) and individual symptoms for eyes (P < 0.02), nose (P < 0.04) and chest (P < 0.01) as well as combined symptom and medication scores (P < 0.002) remained lower in the group with previous SIT. Only 23% of patients with previous pollen-asthma who had received SIT experienced pollen-associated lower respiratory tract symptoms compared to 70% in the control group (P < 0.05). There was no significant difference in the use of pharmacological treatment during the pollen season except for asthma medication. The average visual analog scale was lower in the post-SIT group (P < 0.05). Six years after cessation of SIT the immediate skin response to grass pollen remained decreased compared to the reaction of the controls (P < 0.01). There was also a tendency for higher allergen concentration to provoke a conjunctival response in the post-SIT group but without reaching statistical significance. Eight years after commencement of SIT, 61% of the initially pollen-monosensitized children had developed new sensitization to perennial allergens compared to 100% in the control group (P < 0.05). There is still a significant clinical benefit six years after discontinuation of preseasonal grass pollen immunotherapy in childhood. SIT in children with pollen-allergy reduces onset of new sensitization and therefore has the potential to modify the natural course of allergic disease.

Antihistamines as anti-inflammatory agents.

Although specific immunotherapy is the only aetiological treatment for allergic disorders, the underlying mechanisms are not fully understood. Specific immunotherapy induces changes in lymphocyte Th subsets from Th2 to Th1/Treg. Whether differences in immunological patterns underlie patient response to immunotherapy has not yet been established. We studied the immunological changes occurring during a 1-year period of Dermatophagoides pteronyssinus (DP) immunotherapy and their relation with clinical outcome. We included 34 patients with DP allergy who received subcutaneous specific immunotherapy (SCIT) for 1year. Following treatment, patients were classified as responders or non-responders. Fourteen allergic subjects who did not receive SCIT were included as controls. Peripheral blood was obtained at 0, 1, 3, 6 and 12months and cultured with nDer p 1. Phenotypic changes, cytokine production and basophil response were analysed by flow cytometry; transcription factors were measured by mRNA quantification. Serum immunoglobulin levels were also measured. After 1year of SCIT, 82% of cases showed improved symptoms (responders). Although increases in sIgG4 were observed, BAT reactivity was not modified in these patients. Increases in T-BET/FOXP3 as well as nDer p 1-specific Th1/Treg frequencies were also observed, along with a decrease in Th2, Th9 and Th17. These changes corresponded to changes in cytokine levels. Patients who respond well to DP-SCIT show immunological differences compared to non-responders. In responders, basal differences include a lower frequency of Th1 and higher frequencies of Th2, Th9 and Th17 cells. After 1year of treatment, an increased production of sIgG4 was observed in responders, along with a change in Th2 response towards Th1/Treg.

In a retrospective study, asthmatic patients allergic to either house-dust mite (HDM) (Dermatophagoides pteronyssinus) (n = 34) or to both HDM and grass pollen (GP) (n = 14), and who were treated with specific immunotherapy (SIT) during childhood (mean duration of SIT: 61 +/- 9.70 months), were re-evaluated in early adulthood after mean cessation of SIT for 9.3 +/- 2.76 years. The results were compared to those of a control group of asthmatic patients (n = 42) with comparable asthma features, who were treated with appropriate antiasthmatic drugs during childhood, but who never received SIT. Re-evaluation was carried out with a standardized questionnaire, skin prick tests (SPT), and lung-function assessments. At the time of re-evaluation, the mean age in the SIT-treated group was 23.1 +/- 3.50 years; in the control group, it was 22.7 +/- 3.40 years. At re-evaluation, the risk of frequent asthmatic symptoms was three times higher in the control group than in the SIT-treated group (prevalence ratio: 3.43; P = 0.0006). The frequent use of antiasthmatic medication was also more pronounced in the control group, although the difference was not statistically significant (P=0.38). Lung-function parameters and results of SPT with HDM were comparable in both groups. It is concluded that SIT has long-term effects on asthmatic symptoms in young adults.

High-dose sublingual immunotherapy with single-dose aqueous grass pollen extract in children is effective and safe: A double-blind, placebo-controlled study

While safety and efficacy of specific immunotherapy (SIT) by the sublingual route in patients with allergic asthma/rhinitis have now been largely documented, the immunological mechanisms have only started to be investigated. Most likely, the allergen captured within the oral mucosa by Langerhans-like dendritic cells (DCs), subsequently mature and migrate to proximal draining lymph nodes, which then induce T lymphocytes with regulatory function. Animal experiments point to enhanced expansion of TGF-β, IL-10 and Fox p3 mRNA in CD4+ T cells, indicators of tolerance, induced by mucosal vaccination. Meanwhile, although there is still no firm proof in human, data on increase in allergeninduced IL-10 and allergen-specific IgA secretion supports the possible role of T regulatory cells in sublingual immunotherapy. Furthermore, detection of high amounts of lipopolysacharide receptor CD14 on oral DCs support the idea of using adjuvants such as mycobacteria along with allergen within the oral cavity, which may further potentiate the immunomodulatory effect. Adjuvants that induce the generation of allergen-specific T regulatory cells have been suggested to increase the success of SIT. Supporting this concept, Mycobacterium vaccae was demonstrated to induce CD4+CD45RBlow T regs that secrete IL-10 and TGF-β.

Specific immunotherapy (SIT) induces immunological changes leading to a decrease in allergen-driven symptoms and medication use. However, the use of arbitrary and variable assay formats and units hampers comparisons between SIT studies. The magnitude of IgG response induced by SIT is not directly linked to clinical improvement, so an increase in allergen-specific IgG(4) should be considered a necessary but not sufficient marker of clinical efficacy. Dose-dependent IgG(4) immune responses should be demonstrated by the manufacturer, not by doctors. Symptom and medication scores are essential end-points for immunotherapy studies, but are subjective, so close association with objective assay measurements will be difficult. Nonetheless, blocking antibody assays combining serology and cellular function may provide a solution for relating immunological assay measurements to clinical outcomes.

Immunotherapy with T-cell-reactive peptides derived from allergens.

According to the maximum tolerated dose (MTD) achieved, we assessed the changes in clinical and laboratory parameters, induced by specific immunotherapy (SIT), in a group of 43 asthmatic patients sensitized to Dermatophagoides pteronyssinus, over a period of 18 months. A standardized extract (100 Bu/ml; 40 micrograms/ml of Der p 1; 20 micrograms/ml of Der p 2) was used. The patients were divided into two groups: the high-dose immunotherapy (HDI) group (MTD > or = 4 micrograms Der p I) and the conventional immunotherapy (CI) group (MTD < 4 micrograms Der p 1). Changes in clinical severity index, medication, and symptom scores; in cutaneous and conjunctival reactivity; and in the levels of specific IgE, IgG, IgG1, and IgG4 to D. pteronyssinus (Der p 1 and Der p 2) were measured (ELISA monoclonal antibodies). Safety was monitored according to the EAACI guidelines. The range of the MTD was 0.8-16 micrograms of Der p 1. Ninety percent of the patients tolerated a dose of 3.2 micrograms, but only 18% of the patients reached a maintenance dose of 16 micrograms. The medians of the accumulated dose were 197 micrograms of Der p 1 for the HDI group, and 50 micrograms for the CI group. Conjunctival and cutaneous reactivity was significantly lowered (P < 0.001) after SIT, as were the clinical severity score and medication score in both groups, without significant differences between the groups, except for cutaneous reactivity. Levels of specific IgE decreased significantly (P < 0.01) in both groups, again without significant differences between the groups. The range of the increase in medians of specific IgG, IgG1, and IgG4 was 4.4-120-fold for the HDI group and 3-24-fold for the CI group (P < 0.01). The increase in the levels of Der p 1 and Der p 2 IgG4 were correlated to the changes in cutaneous and conjunctival reactivity (P < 0.01). These results show that a maintenance dose of 3.2 micrograms Der p 1 (8 BU) can induce pronounced clinical and immunologic changes with an excellent safety profile.

Early symptoms of food allergy, including diarrhea, are caused by IgE-mediated anaphylactic reactions. To clarify the mechanisms of IgE-mediated anaphylactic reactions in the intestine induced by orally administered antigen, a mouse model was established by s.c. implantation of a murine hybridoma capable of producing monoclonal anti-trinitrophenyl IgE antibody. Morphologic and immunologic changes in the intestine, as well as the effect of the soluble high affinity IgE receptor alpha chain, were investigated after oral challenge with antigen in this mouse model. Diarrhea, a decrease in s.c. blood flow, an increase in vascular permeability, a substantial increase in serum histamine levels, and noticeable infiltration of mast cells and IgE-bearing cells into the lamina propria were observed around 30 min after antigen challenge. However, these changes were efficiently prevented by pretreatment of the mice with the soluble high affinity IgE receptor alpha chain. These findings suggested that oral administration of antigen actually induced anaphylactic shock in our mouse model. This reaction was most likely to be mediated by mast cell activation, in response to the IgE-antigen complex, and a soluble form of the high-affinity IgE receptor efficiently prevented this IgE-mediated anaphylactic reaction by trapping free IgE.