[Allergen specific immunotherapy for rhinitis allergica : New applications]. / Allergenspezifische Immuntherapie bei Rhinitis allergica : Neue Applikationsformen.

BACKGROUND: Allergic diseases are among the most common diseases of humans. The immune response towards allergens is regulated by T-lymphozytes and characterized by an interleukin (IL)-4, IL-5 and IL-13 dominated Th2 cytokine profile. RESULTS: Allergen-specific immunotherapy (AIT) is the only causative treatment option and able to change the course of disease, e. g. to prevent the development of asthma and new sensitizations. The intralymphatic delivery of allergenes named intralymphatic immunotherapy (ILIT) has been evaluated in clinical trials and was demonstrated to be a highly potent application route with low effort and side effects while having equal efficacy if compared with current standard AIT forms. However, studies that verify important questions like optimal dose, new allergen forms, use of adjuvants etc. are still missing. Moreover, it has to be evaluated, whether different indications like rhinitis, or atopic dermatitis are suitable for ILIT and whether it is useful in children. Epicutaneous immunotherapy (EPIT) is a possible alternative application form. It is minimally invasive and basically consists of the affixation of allergen containing patches to the epidermis over 6 weeks. From the studies performed so far, the authors concluded, that epicutaneous immunotherapy is safe and efficacious in a dose-dependent manner after 6 patches only. CONCLUSIONS: AIT is accepted to be the only causative treatment option for allergies. New application routes in ILIT and EPIT may become more important and allow for different delivery methods in the future, however further clinical studies are required and in preparation.

Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials.

The results of our third trial on epicutaneous allergen-specific immunotherapy (EPIT) will be presented and discussed in the context of our previous trials. This monocentric, placebo-controlled, double-blind phase I/IIa trial included 98 patients with grass pollen rhinoconjunctivitis. Prior to the pollen season 2009, patients received six patches (allergen extract: n = 48; placebo: n = 50) with weekly intervals, administered onto tape-stripped skin. Allergen EPIT produced a median symptom improvement of 48% in 2009 and 40% in the treatment-free follow-up year 2010 as compared to 10% and 15% improvement after placebo EPIT (P = 0.003). After allergen EPIT but not placebo EPIT, conjunctival allergen reactivity was significantly decreased and allergen-specific IgG4 responses were significantly elevated (P < 0.001). In conclusion, our three EPIT trials found that allergen EPIT can ameliorate hay fever symptoms. Overall, treatment efficacy appears to be determined by the allergen dose. Local side-effects are determined by the duration of patch administration, while risk of systemic allergic side-effects is related to the degree of stratum corneum disruption.

Immune regulation by intralymphatic immunotherapy with modular allergen translocation MAT vaccine.

BACKGROUND: Allergen-specific immunotherapy (SIT) faces problems related to side effects and limited efficacy. Direct administration of allergen extracts into lymph nodes induces increased specific IgG production and T-cell responses using significantly lower allergen doses. METHODS: In this study, mechanisms of immune regulation by MAT vaccines in vitro and in allergen-SIT of cat-allergic rhinitis patients, who received 3 inguinal intra-lymph node injections of MAT-Fel d 1 vaccine, were investigated in PBMC and cell cultures for specific T-cell proliferation, Fel d 1-tetramer-specific responses, and multiple immune regulatory molecules. RESULTS: MAT-Fel d 1 vaccine was efficiently internalized by antigen-presenting cells. This was followed by precaspase 1 cleavage to caspase 1 and secretion of IL-1ß, indicating inflammasome activation. Mat-Fel d 1 induced specific T-cell proliferation and an IL-10- and IFN-γ-dominated T-cell responses with decreased Th2 cytokines at 100 times lower doses than Fel d 1. Induction of immune tolerance by MAT-Fel d 1-ILIT involved multiple mechanisms of immune suppression. Early Fel d 1-specific T-cell activation was followed by full T-cell unresponsiveness to allergen after 1 year in the MAT-Fel d 1 group, characterized by increased allergen-specific T regulatory cells, decreased circulating Fel d 1 tetramer-positive cells, increased IL-10 and FOXP3 expression, and change in the HR2/HR1 ratio toward HR2. CONCLUSIONS: This study demonstrates the induction of allergen tolerance after 3 intra-lymph node injections of MAT-Fel d 1 vaccine, mediated by increased cellular internalization of the allergen, activation of inflammasome, and generation of allergen-specific peripheral T-cell tolerance.

A critical appraisal of analyzing nasal provocation test results in allergen immunotherapy trials.

BACKGROUND: The statistical analysis of nasal provocation tests is very complex. We compared the conventional analysis with the maximally selected test statistics and the hierarchical ordered logistic model. METHODS: We re-analyzed data from a trial with 112 patients suffering from grass pollen allergy. The patients had been randomized to receive either intralymphatic immunotherapy (ILIT) or subcutaneous immunotherapy (SCIT). RESULTS: The conventional analysis indicated that the logarithmized ratio between the pre- and the post-treatment threshold concentration was significantly lower for ILIT than for SCIT. The maximally selected test statistics was used to test different threshold symptom scores that would imply positive clinical symptoms at the given allergen concentration. A threshold score of 3 maximised the difference in improvement between the ILIT and the SCIT groups. The hierarchical ordered logistic model does not take threshold allergen concentrations as the basis for analysis, but the single scores measured at each concentration. This approach simultaneously considers the treatment effect (ILIT versus SCIT), the time effect (pre- versus post-treatment), and the dose effect (different allergen concentrations). The hierarchical ordered logistic model revealed that the clinical improvement was greater after ILIT than after SCIT. CONCLUSION: As the choice of method can affect the outcome, guidelines for analysis are highly needed.

IgG-mediated down-regulation of IgE bound to mast cells: a potential novel mechanism of allergen-specific desensitization.

BACKGROUND: Allergen-specific IgGs are known to inhibit IgE-mediated mast cell degranulation by two mechanisms, allergen-neutralization and engagement of the inhibitory FcγRIIB recruiting the phosphatase SHIP-1. Here we unravel an additional mechanism of IgG-mediated mast cell desensitization in mice: down-regulation of allergen-specific IgE. METHODS: Mast cells were loaded in vitro and in vivo with monoclonal IgE antibodies specific for Fel d1 and exposed to immune complexes consisting of Fel d1-specific IgG antibodies recognizing different epitopes. Down regulation of IgE was followed by flow cytometry. RESULTS: Mast cells loaded with 2 different IgE antibodies efficiently internalized the IgE antibodies if exposed to recombinant Feld d1. In contrast, no down-regulation occurred if mast cells were loaded with IgE antibodies exhibiting a single specificity before stimulation with recombinant Fel d1 [corrected]. Interestingly, however, IgEs of a single specificity were rapidly down-regulated in vitro and in vivo in the presence of Fel d1-specific monoclonal IgGs recognizing another epitope on Fel d1. Despite FceRI-internalization, little calcium flux or mast cell degranulation occurred. FcγRIIB played a dual role in the process since it enhanced IgE internalization and prevented cellular activation as documented by the inhibited calcium flux and mast cell degranulation. Similar observations were made in the presence of low concentrations of IgEs recognizing several epitopes on Fel d1. CONCLUSION: We demonstrate here that Fel d1-specific IgG antibodies interact with FcγRIIB which (i) promotes IgE internalization; and (ii) inhibits mast cell activation. These results broaden our understanding of allergen-specific desensitization and may provide a mechanism for long-term desensitization of mast cells by selective removal of long-lived IgE antibodies on mast cells.

[Immunotherapy of allergic rhinitis without allergens? : new options for immunomodulation by vaccination with virus-like particles and CpG motifs]. / Immuntherapie der allergischen Rhinitis ohne Allergene? : Neue Möglichkeiten einer Immunmodulation durch Vakzinierung mittels "virus-like particles" und CpG-Motiven.

BACKGROUND: Allergen-specific immunotherapy is generally accepted as the only causal therapy for allergic rhinitis. Up to now there has been a dogma in immunotherapy for inhalation allergies that at least allergen components are necessary for effective therapy. This dogma could, however, be swayed by current results of effective immunotherapy without allergens. Virus-like particles (VLP) represent a novel and interesting aspect for immunotherapy for inhalation allergies. AIM: Initial experiences with successful immunotherapy without allergens are available. This article describes the currently available clinical experiences with bacteriophage VLPs filled with oligonucleotides which contain CpG motifs with tumor antigens on the surface for the treatment of allergic rhinitis. RESULTS: Vaccination with VLPs was found to be well tolerated, immunogenic and effective for prophylactic treatment of various infections. Bacteriophage VLPs filled with CpG motifs with tumor antigens on the surface led clinically to an induction of specific T-cells in tumor patients and were successfully implemented as adjuvants during prophylactic vaccinations. CONCLUSION: The VLP technique in combination with the use of CpG motifs could contribute to the causal treatment of complex diseases, such as malignancies, autoimmune diseases and allergies.

The contact sensitizer diphenylcyclopropenone has adjuvant properties in mice and potential application in epicutaneous immunotherapy.

BACKGROUND: Epicutaneous vaccination has gained increasing interest during the past decade as it offers a safe, needle-free, and patient-friendly alternative to invasive vaccine administrations. Recently, the safety and early efficacy of epicutaneous immunotherapy were also demonstrated in patients with hay fever, as an alternative to conventional subcutaneous allergen-specific immunotherapy (SCIT). One major challenge to epicutaneous vaccination is the barrier function of the stratum corneum, which must be overcome either by abrasive methods or by hydration. Such barrier function of the stratum corneum also hampers the use of common adjuvants used to enhance the efficacy of vaccination. METHODS: In a mouse model of allergy, we tested the adjuvant potential of diphenylcyclopropenone (DCP), a strong contact sensitizer, which is currently used for the treatment of a T cell-mediated hair loss disease (alopezia areata). RESULTS: Diphenylcyclopropenone enhanced antigen-specific IgG2a antibody responses as well as IL-10 cytokine production after epicutaneous immunization with ovalbumin (OVA). Epicutaneous allergen-specific immunotherapy (EPIT) with OVA and DCP also protected sensitized mice from anaphylaxis and asthma. The protective effect was more robust than that of conventional SCIT, which did not significantly alleviate the symptoms of allergy in the murine models of anaphylaxis and asthma. CONCLUSIONS: This preclinical study confirmed previous clinical data that have demonstrated the potential of the skin as a target for allergen immunotherapy. The study also suggests that epicutaneous immunization or immunotherapy can be improved when an appropriate adjuvant such as DCP is used.

Epicutaneous allergen administration: is this the future of allergen-specific immunotherapy?

IgE-mediated allergies, such as allergic rhinoconjunctivitis and asthma, have become highly prevalent, today affecting up to 30% of the population in industrialized countries. Allergen-specific immunotherapy (SIT) either subcutaneously or via the sublingual route is effective, but only few patients (<5%) choose immunotherapy, as treatment takes several years and because allergen administrations are associated with local and, in some cases, even systemic allergic side-effects because of allergen accidentally reaching the circulation. In order to resolve these two major drawbacks, the ideal application site of SIT should have two characteristics. First, it should contain a high number of potent antigen-presenting cells to enhance efficacy and shorten treatment duration. Secondly, it should be nonvascularized in order to minimize inadvertent systemic distribution of the allergen and therefore systemic allergic side-effects. The epidermis, a nonvascularized multilayer epithelium, that contains high numbers of potent antigen-presenting Langerhans cells (LC) could therefore be an interesting administration route. The present review will discuss the immunological rational, history and actual clinical experience with epicutaneous allergen-specific immunotherapy.

[Allergen specific immunotherapy: new approaches]. / Allergenspezifische Immuntherapie: Auf neuen Wegen in die Zukunft.

Specific immunotherapy (SIT) is the only disease-modifying and causal treatment of IgE mediated allergic diseases. Soon this treatment will turn 100 years old. Subcutaneous immunotherapy is still considered to be the gold standard of SIT. With the intention to improve efficacy, safety and desirability for patients, new strategies such as epicutaneous immunotherapy, i.e. administration of allergens using a skin patch, are under investigation in clinical trials at the Zurich University Hospital.

Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen-specific immunotherapy in humans: a phase I/IIa clinical trial.

BACKGROUND: B-type CpG oligodeoxynucleotides (ODN) is currently used in clinical trials because of its prolonged half-life, which is due to its phosphorothioate backbone. A-type CpG ODN is a stronger inducer of IFN but has an unstable phosphodiester backbone that has so far prohibited its clinical use. However, upon association with virus-like particles (VLP) consisting of the bacteriophage Qbeta coat protein, A-type CpG ODN can be stabilized and can become an efficient adjuvant in mice. Therefore, the phase I/IIa study presented represents the first test of A-type CpGs in humans. OBJECTIVE: To test the safety, tolerability and clinical efficacy of QbG10 as an adjuvant for subcutaneous immunotherapy with a house dust mite (HDM) allergen extract in allergic patients. METHODS: A single centre, open-label phase I/IIa study evaluated the safety, tolerability and clinical efficacy of QbG10 as an adjuvant to immunotherapy with a subcutaneous HMD allergen extract in 20 patients suffering from HDM allergy. Twenty-one patients were enrolled between March and July 2005. Individual immunotherapy lasted 10 weeks. Clinical end-points included questionnaires, conjunctival provocation, skin prick tests and the measurement of allergen-specific IgG and IgE. RESULTS: QbG10 was well tolerated. Almost complete tolerance to the allergen was observed in conjunctival provocation testing after treatment with QbG10, and symptoms of rhinitis and allergic asthma were significantly reduced. Within 10 weeks of therapy, patients were nearly symptom-free and this amelioration lasted for at least 38 weeks post-treatment. Following injections of QbG10 and HDM allergen extract, allergen-specific IgG increased, while there was a transient increase in allergen-specific IgE titres. Skin reactivity to HDM was reduced. CONCLUSION: The subcutaneous application of HDM allergen, together with A-type CpG ODN packaged into VLP, was safe. All patients achieved practically complete alleviation of allergy symptoms after 10 weeks of immunotherapy. This promising clinical outcome calls for larger placebo-controlled phase II studies.

Targeting the MHC class II pathway of antigen presentation enhances immunogenicity and safety of allergen immunotherapy.

BACKGROUND: Current s.c. allergen-specific immunotherapy (SIT) leads to amelioration of IgE-mediated allergy, but it requires numerous allergen injections over several years and is frequently associated with severe side-effects. The aim of this study was to test whether modified recombinant allergens can improve therapeutic efficacy in SIT while reducing allergic side-effects. METHODS: The major cat allergen Fel d 1 was fused to a TAT-derived protein translocation domain and to a truncated invariant chain for targeting the MHC class II pathway (MAT-Fel d 1). The immunogenicity was evaluated in mice, while potential safety issues were assessed by cellular antigen stimulation test (CAST) using basophils from cat-dander-allergic patients. RESULTS: MAT-Fel d 1 enhanced induction of Fel d 1-specific IgG2a antibody responses as well as the secretion of IFN-gamma and IL-2 from T cells. Subcutaneous allergen-specific immunotherapy of mice using the modified Fel d 1 provided stronger protection against anaphylaxis than SIT with unmodified Fel d 1, and MAT-Fel d 1 caused less degranulation of human basophils than native Fel d 1. CONCLUSION: MAT-Fel d 1 allergen enhanced protective antibody and Th1 responses in mice, while reducing human basophil degranulation. Immunotherapy using MAT-Fel d 1 allergen therefore has the potential to enhance SIT efficacy and safety, thus, shortening SIT. This should increase patient compliance and lower treatment costs.

Medication with antihistamines impairs allergen-specific immunotherapy in mice.

BACKGROUND: Histamine released from activated mast cells and basophils is an important mediator in allergy. Therefore, antihistamines are efficiently and widely used to suppress allergic symptoms. OBJECTIVE: This study evaluated the role of antihistamines in sensitization against allergens and in the efficiency of allergen-specific immunotherapy. METHODS: CBA mice were sensitized and de-sensitized with bee venom allergen extracts and the major allergen phospholipase A2. Clemastine was used to test the effect of a histamine-1 receptor antagonist on the immune responses to phospholipase A2. RESULTS: The results demonstrated that sensitization against bee venom was strongly enhanced during treatment with antihistamines. Clemastine increased IgE production while decreasing IgG2a production against bee venom. This T-helper type 2 shift of the humoral response appeared to be caused by reduced IFN-gamma and enhanced IL-4 secretion from allergen-specific T cells. We also found reduced TNF-alpha, IL-6 and major histocompatibility complex class-II expression by macrophages. In sensitized mice, the efficiency of allergen-specific immunotherapy was reduced by clemastine treatment. CONCLUSION: Antihistamines may enhance allergic sensitization and reduce the efficiency of allergen-specific immunotherapy. Future studies will need to demonstrate to what extent pre-medication with antihistamine also affects allergen-specific immunotherapy in humans.

Analysis of the relationship between pollinosis and date of birth in Switzerland.

BACKGROUND: The first months of life may represent a vulnerable period in the development of atopic diseases. The objective of this study was to examine the relationship between the month of birth and the development of birch and grass pollen allergy in the Swiss population. METHODS: Data from the Swiss Study on Air Pollution and Lung Diseases in Adults(SAPALDIA) as well as the Swiss Study on Childhood Allergy and Respiratory Symptoms with Respect to Air Pollution and Climate (SCARPOL) were used. A logistic regression was calculated with grass and birch pollen sensitisation (positive skin prick test) or allergy (positive skin prick test and allergic symptoms) as outcome variables and the season of birth as predictor variable. The contribution of the season of birth on pollinosis was further adjusted for well-known risk factors and potential confounding variables. RESULTS: The logistic regression revealed a significant effect of the season of birth on birch pollen sensitisation and an effect of borderline significance on birch pollen allergy, i.e. subjects born in the pollen season (March to April) showed an increased risk of being sensitised/allergic to birch pollen. The results also indicated a tendency towards an increased risk for subjects born in the grass pollen season (May to June) to develop grass pollen allergy. CONCLUSION: Our results support the hypothesis that the first few months of life constitute a sensitive period, during which inhalative exposure to certain allergens may predispose to the subsequent development of atopic respiratory disease.

Antimicrobial silk clothing in the treatment of atopic dermatitis proves comparable to topical corticosteroid treatment.

BACKGROUND: Atopic dermatitis (AD) is aggravated by mechanical irritation and bacterial colonization. OBJECTIVE: This study compared the efficacy of an antimicrobial silk fabric (DermaSilk) with that of a topical corticosteroid in the treatment of AD. METHODS: Fifteen children were enrolled and wore a dress, where the left side was made of DermaSilk and the right side was made of cotton. The right arm and leg were treated daily with the corticosteroid mometasone for 7 days. The treatment efficacy was measured with a modified EASI (Eczema Area and Severity Index) and with an assessment by the patients/parents and by a physician. All patients were evaluated at baseline, as well as 7 and 21 days after the initial examination. RESULTS: All parameters showed that, irrespective of the treatment, there was a significant decrease of eczema after 7 days. No significant difference between DermaSilk-treated and corticosteroid-treated skin could be observed. CONCLUSION: DermaSilk showed potential to become an effective treatment of AD.

Coated textiles in the treatment of atopic dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with increasing prevalence over the last few decades. Various factors are known to aggravate the disease. In particular, wool and synthetic fabrics with harsh textile fibres, aggressive detergents and climatic factors may exacerbate AD. Cutaneous superinfection, particularly with Staphylococcus aureus, is also recognized as an important factor in the elicitation and maintenance of skin inflammation and acute exacerbations of AD. The severity of AD correlates with S. aureus colonization of the skin. Beside the treatment of AD patients with creams and emollients, new developments in the textile industry may have therapeutic implications. Silk or silvercoated textiles show antimicrobial properties that can significantly reduce the burden of S. aureus, leading to a positive effect on AD. Silver products have been used as wound dressing, whereby silver has antiseptic properties, and drug resistance is hardly found. Padycare textiles consist of micromesh material containing woven silver filaments with a total silver content of 20%. In vitro studies of these silver-coated textiles demonstrated a significant decrease in S. aureus and Pseudomonas aeruginosa as well as Candida albicans. Silk has been increasingly implemented in medical treatment of AD thanks to its unique smoothness that reduces irritation. Silk can be coated with antimicrobials (Dermasilk). The combination of the smoothness of silk with an antimicrobial finish appears to make an ideal textile for patients suffering from AD.

Efficacy and safety of allergen-specific immunotherapy in rhinitis, rhinoconjunctivitis, and bee/wasp venom allergies.

The prevalence of allergic diseases, such as rhinoconjunctivitis, is increasing worldwide, particularly in Westernized countries, where more than 30% of the population is affected. Insect venom allergy is also very common, affecting up to 5% of the population. Allergen-specific immunotherapy is the only immunomodulatory treatment that may alter the natural course of allergic disease, for example by preventing the development of asthma in rhinitic patients. Nonetheless, the risk-benefit ratio for subcutaneous immunotherapy has changed little from when it was first developed a century ago. However, the rapid evolution of new developments, including new methods of administration and new forms of antigen to stimulate the immune system, now offers improvements in both the safety and the efficacy of specific immunotherapy. These developments include the sublingual administration of the relevant antigens, which has a superior safety profile than the original subcutaneous route. This may enable higher dosages to be used over shorter treatment periods, with a lower risk of anaphylactic reactions. Improvements in the purity, specificity, and immunogenicity of the antigens, often as a result of advances in biotechnology, coupled with the development of new adjuvants, may further increase the efficacy of this form of treatment. This review describes and discusses these new developments in the context of the many recent advances in our understanding of the mechanisms by which immunotherapy appears to act.

Direct intralymphatic injection of peptide vaccines enhances immunogenicity.

Research to enhance the efficiency of vaccines focuses mainly on improving either the adjuvant or the type and form of the antigen. This study evaluates the influence of the administration route on the efficiency of a peptide-based vaccine. Peptide vaccines are generally administered subcutaneously or intradermally, from where they must reach secondary lymphatic organs to induce an immune response. We analyzed the efficacy of peptide vaccines administered directly into a lymph node. Using a MHC class I-binding peptide from lymphocytic choriomeningitis virus, we found that intralymphatic injection enhanced immunogenicity by as much as 10(6) times when compared to subcutaneous and intradermal vaccination. Intralymphatic administration induced CD8 T cell responses with strong cytotoxic activity and IFN-gamma production that conferred long-term protection against viral infections and tumors. These results should have immediate implications for clinical immunotherapy of infectious disease and cancer.

Toll-like receptor ligands as adjuvants in allergen-specific immunotherapy.

BACKGROUND: Allergen-specific immunotherapy (SIT) leads to long-term amelioration of T-helper type 2 (Th2)-mediated allergic symptoms and is therefore recommended as a first line therapy for allergies. The major disadvantage of SIT is its low efficiency, requiring treatment over years. OBJECTIVE: In this study, we evaluated the potential of Toll-like receptor (TLR) ligands to facilitate Th1-type immune responses. METHODS: The immunogenicity and therapeutic potential of the major bee venom allergen phospholipase A2 (PLA2) combined with various TLR ligands were tested in mice and compared with immune responses induced by conventional aluminium-based preparations. RESULTS: Regarding total IgG against PLA2, TLR2/4-binding lipopolysaccharide and TLR3-binding polyriboinosinic polyribocytidylic (PolyI:C) were the superior adjuvants for prophylactic vaccination. However, TLR9-binding phosphorothioate-modified cytosine-guanosine-rich oligonucleotide (CpG), TLR-3-binding PolyI:C, and TLR2/6-binding peptidoglycan skewed the immune responses more towards IgG2a isotype and Th1 cytokines. Furthermore, in a therapeutic approach, CpG, PolyI:C and TLR7/8-binding 3M003 had immune modulating properties as they suppressed established IgE titres. CONCLUSION: The potential of TLR ligands to adjuvate the immunogenicity of bee venom PLA2 and to skew the Th1-Th2 balance proved very heterogeneous. With respect to SIT, CpG, PolyI:C, and 3M003 were very promising. Hence, TLR ligands should be considered as adjuvants or immune modulators in SIT in human as to improve its efficiency regarding the Th1-Th2 balance of the immune response with a likely effect on therapy duration.