Recombinant house dust mite allergens
Section snippets
Immunotherapy for HDM allergy
The most frequent triggers for asthma attacks in subjects with house dust mite (HDM) allergy are thought to be non-allergenic nocuous insults acting on inflamed airway such as infections and irritants [1]. This differs from pollen-induced rhinitis, venom-induced anaphylaxis and cat allergy where the symptoms are most frequently caused by hypersensitivity reactions directly triggered by the allergen. It is therefore probable that the mechanism for optimal immunotherapy will be different.
Allergen specificity
The objective of specific immunotherapy is to determine the allergen responsible for the sensitization of patient and then to administer it in a way that stimulates the patient’s immune system to turn off or counter-act harmful response to the allergen. Evidence that the therapy used today, such as the injection of a succession of progressively increasing doses of allergen, is mediated by allergen-specific changes in the responses of allergen reactive antibodies and T cells is surprisingly
Advantages from recombinant allergens
Broadly the advantages would be (1) the use of defined reproducible formulations, (2) the use of balanced formulations, (3) access to large amounts of allergen, (4) removal of non-allergen inflammatory stimuli and (5) entree to genetically modified allergens.
The current standardisation procedures for extracts measure their ability to induce skin test responses not their composition. A recent survey found that ratio of the two major allergens from Dermatophagoides pteronyssinus Der p 1 & 2
The important allergens
The allergenic potential of different HDM allergens has been assessed by quantitative IgE binding with panels and purified and recombinant allergens [29], [30], [31], [32] and by absorption of the IgE staining moieties on 2-D western blotting [33]. The IgE binding to Der p 1 and Der p 2 has been found to constitute 50–60% of the IgE binding to all of the HDM allergens for essentially all HDM allergic subjects with the summated titres to Der p 1 and 2 tightly correlating with the binding to
Mite species and variant allergens
Most HDM allergy is caused by sensitization to the pyroglyphid mite species Dermatophagoides pteronyssinus and D. farinae. There are defined regions where they co-exist in homes with the glycyphagoide mite Blomia tropicalis which because of their genetic disparity and differences in allergen production are a separate source of allergen. As recently reviewed [50] D. pteronyssinus is the most prevalent species in maritime western and southern Europe, South America, Africa, and Australasia. In
Immunotherapy with major allergens
It would be advantageous to conduct immunotherapy with one or two allergens. This would not only have the obvious advantage of only having to make 2 antigens (with variants) but it also might be more effective than administering a more complex mixture. Therapy with fewer allergens would both elicit fewer allergic side effects and reduce the production of inflammatory mediators that activate dendritic cells and thereby antagonise the induction of energy [71]. This could be the mechanism behind
Production of recombinant HDM allergens
Recombinant group 1 allergens must be produced with its 80 amino acid residue proenzyme sequence that then needs to be cleaved to create the mature protein. This has most efficiently been accomplished with the host Pichia pastoris and the removal of the single N-glycosylation site of the mature enzyme [85], [86]. Der f 1 has either been produced as a mature protein with the pro-region self cleaved during its synthesis by P. pastoris [85] or as proenzyme that then had to be cleaved by an acid
Production of allergens for therapeutic trials
Recombinant biopharmaceuticals to be used in clinical trials have to be produced under the principles of cGMP (current Good Manufacturing Practice). GMP is an internationally harmonized manufacturing standard which ensures the fundamental quality criteria of pharmaceutical products (i.e. identity, purity, safety, strength, potency and stability). In the major guideline of the International Conference on Harmonisation (ICH Q7A), the fundamental GMP principles are regularized [101]. Although
Strategies for modified allergens
Recombinant technology is ideally suited to provide modified allergens that will enable new treatments. The modifications can be aimed at several strategies. They can be modified to reduce their binding to IgE antibodies and thus allow higher doses to be delivered without anaphylactoid side effects or they can be modified to preferentially target control mechanisms such as the induction of blocking IgG antibodies [106], immune deviation away from a Th2 response [107], [108], anergy [109], [110]
Modified house dust mite allergens
So far, hypoallergenic derivatives have only been produced from the group 1 and 2 allergens (Table 1).
Immunogenicity of hypoallergens
Hypoallergenic derivatives need to be evaluated in vitro and in vivo, for their allergenic activity and their immunogenicity (Table 1). Importantly immunization of animals (e.g. mice) with hypoallergenic derivatives of HDM allergens coupled to adjuvants have to show that they can induce blocking antibodies, which recognize the wild type allergen and inhibit patients’ IgE binding to the allergen. So far, this has been shown for the proform of Der p 1 [146], [147], for Der p 1 peptides coupled to
Conclusions
Recent advances using quantitative methods have consolidated the findings that for D. pteronyssinus the responses of most allergic subjects follow an allergen hierarchy where over half the IgE is directed to Der p 1 and 2 and most of the rest is directed to the allergens Der p 4, 5, 7 and 21. The proportionality and restricted spectrum is retained for high and low responses and for severe and mild asthmatics. This provides a sound platform for developing formulations of recombinant allergens
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2022, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Inoculation of HDM into the airways initiates extensive innate and adaptive immune responses in mice [6,7]. HDM-induced asthma models are used to study eosinophilic steroid-responsive asthma which occurs in about half of patients [8,9]. Previous studies indicated that antigen composition used for sensitization defines the severity and the outcome of asthma.
Degradation of bacterial permeability family member A1 (BPIFA1) by house dust mite (HDM) cysteine protease Der p 1 abrogates immune modulator function
2020, International Journal of Biological MacromoleculesCitation Excerpt :Our data corroborate this finding, suggesting that HDM-mediated BPIFA1 degradation is temperature-insensitive and that, as long as a sufficient amount of HDM is present, protein substrate such as BPIFA1 can be cleaved at low as 4 °C, which likely leads to the perennial allergy problems. More than 20 groups of HDM allergens have been identified to date, at least four of which are known to express catalytically competent proteinase activity [13,35,36]. These components exert profound effects on airways, which promotes allergic sensitization [13,37].
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2020, Allergologia et ImmunopathologiaIgE binding activities and in silico epitope prediction of Der f 32 in Dermatophagoides farinae
2019, Immunology LettersCitation Excerpt :Several decades later, Voorhorst and Miyamoto identified that house dust mites (HDMs) produced allergens as a causative antigen in bronchial asthma [2,3]. HDMs represent an indoor major allergen source for humans, which induce allergic diseases such as asthma, dermatitis, and rhinitis [4,5]. Thirty-five allergens from the Der f group (Der f 1–4, 6–8, 10–11, 13–18, and 20–36) have been identified and named in the Allergen Nomenclature Database (http://www.allergen.org).
Identification of a novel cofilin-related molecule (Der f 31) as an allergen from Dermatophagoides farinae
2018, ImmunobiologyCitation Excerpt :House dust mite (HDM) is considered to be the most important cause of allergic disease such as allergic rhinitis (Vrtala et al., 2014; An et al., 2013).
Evolution and predictive value of IgE responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life
2017, Journal of Allergy and Clinical Immunology