A Hypoallergenic Derivative of the Major Allergen of the Dust Mite &lt;i&gt;Lepidoglyphus destructor&lt;/i&gt;, Lep d 2.6Cys, Induces Less IgE Reactivity and Cellular Response in the Skin than Recombinant Lep d 2

Kronqvist, Malin; Johansson, E.; Whitley, Paul; Olsson, Sven-Eric; Gafvelin, Guro; Scheynius, Annika; Hage, Marianne van

doi:10.1159/000049493

Cited by 9 publications

(3 citation statements)

References 38 publications

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“…Hypoallergens displaying a decreased IgE-binding activity and a conserved T cell reactivity were generated for the nonspecific lipid transfer protein Par j 1 from P. judaica pollen [85] and the major latex allergen Hev b 6.02 [86]. Disulfide bonds present in the group 2 allergens of mites were also destroyed by site-directed mutagenesis to destabilize the antigenic structure and ablate IgE binding of Der p 2 [87], Der f 2 [88], and Lep d 2 [89,90]. …”

Section: Vaccine Developmentmentioning

confidence: 99%

Recombinant Allergens in Structural Biology, Diagnosis, and Immunotherapy

Tscheppe

Breiteneder²

2017

Int Arch Allergy Immunol

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The years 1988-1995 witnessed the beginning of allergen cloning and the generation of recombinant allergens, which opened up new avenues for the diagnosis and research of human allergic diseases. Most crystal and solution structures of allergens have been obtained using recombinant allergens. Structural information on allergens allows insights into their evolutionary biology, illustrates clinically observed cross-reactivities, and makes the design of hypoallergenic derivatives for allergy vaccines possible. Recombinant allergens are widely used in molecule-based allergy diagnosis such as protein microarrays or suspension arrays. Recombinant technologies have been used to produce well-characterized, noncontaminated vaccine components with known biological activities including a variety of allergen derivatives with reduced IgE reactivity. Such recombinant hypoallergens as well as wild-type recombinant allergens have been used successfully in several immunotherapy trials for more than a decade to treat birch and grass pollen allergy. As a more recent application, the development of antibody repertoires directed against conformational epitopes during immunotherapy has been monitored by recombinant allergen chimeras. Although much progress has been made, the number and quality of recombinant allergens will undoubtedly increase and keep improving our knowledge in basic scientific investigations, diagnosis, and therapy of human allergic diseases.

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Section: Vaccine Developmentmentioning

confidence: 99%

Recombinant Allergens in Structural Biology, Diagnosis, and Immunotherapy

Tscheppe

Breiteneder²

2017

Int Arch Allergy Immunol

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“…Disulfide bonds stabilizing the antigenic structure of major allergens of house dust mites were also targeted by site-directed mutagenesis. Hypoallergenic variants of Der p 2 [54], Der f 2 [55], and Lep d 2 [56,57] were produced and evaluated for their IgEmediated reactions and cellular responses. One potential problem when targeting the conformation of allergens could be the solubility of the final product, as denatured or unfolded proteins tend to form aggregates.…”

Section: Site-directed Mutantsmentioning

confidence: 99%

Modified Recombinant Allergens for Safer Immunotherapy

Ferreira

Briza²,

Inführ³

et al. 2006

IADT

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Molecular cloning and recombinant production of allergens offered new perspectives for the increasing problem of allergies. A variety of preparations are being developed aiming to increase safety and improve efficacy of specific immunotherapy. Recombinant-based approaches are mostly focused on genetic modification of allergens to produce molecules with reduced allergenic activity and conserved antigenicity, i.e. hypoallergens. Studies dealing with genetic modifications of allergen genes reported the production of site-directed mutants, deletion mutants, allergen fragments and oligomers, and allergen chimeras. An alternative to genetic engineering is the chemical modification of pure recombinant allergens. It has been shown that allergens modified with immunostimulatory DNA sequences (allergen-ISS conjugates), which masks IgE epitopes and adds a desirable Th1-inducing character to the allergen molecule. Other chemical modifications include oligomerization by aldehydes (allergoids) and maleylation, which seems to target allergens to particular antigen presenting cells. Several of these modified allergen preparations have been already evaluated for their safety in clinical provocation studies. So far, clinical trials showed the efficacy and safety of immunotherapy with an Amb a 1-ISS conjugate for ragweed pollen-allergic patients. In addition, a preparation consisting of hypoallergenic fragments of Bet v 1 was evaluated for immunotherapy of birch pollen-allergic patients. In parallel, several animal studies have now demonstrated the potential of genetic immunization for allergy treatment in the future.

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“…Interestingly, mutation of the cysteines stabilizing two smaller loops had even larger effects and reduced the allergenicity100-fold. Similar strategies for the homologous allergens from Lepidoglyphus destructor [3] and D. farinae [4] produced a loss of allergenicity and the retention of the ability to stimulate T-cell responses from peripheral blood mononuclear cells (PBMC). Further study on the Der f 2 showed that the mutants could reduce the induction of airway hyperreactivity in mice [5].…”

Section: Mutation Of Disulphide Bondsmentioning

confidence: 99%

Genetically engineered vaccines

Thomas

Hales

Smith

2005

Curr Allergy Asthma Rep

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The application of recombinant DNA technology to allergen research has provided the sequence information and genetic material to produce new types of allergy vaccines. One general strategy has been to use the knowledge to produce synthetic peptides that represent selected T-cell or B-cell epitopes. The production of genetically engineered allergens provides an alternative strategy to construct hypoallergenic vaccines, which can provide a better and less selected representation of the epitopes. Many strategies have been used to produce such hypoallergens, and their ability to reduce allergenicity has been amply demonstrated by skin and nasal provocation tests. The retention of T cell-stimulating activity has also been demonstrated, and a consistent feature of the vaccines has been, despite the reduced immunoglobulin E (IgE)-binding reactivity, the ability to induce anti-allergen IgG antibody. The lead hypoallergens have been polypeptide fragments and trimeric constructs of the birch allergen Bet v 1. A clinical trial with these medicaments has shown the ability to modify IgE and IgG antibody production, skin test reactivity, and symptom scores. This is the first trial of a recombinant allergy vaccine, and it has set a benchmark for further studies. A new generation of hypoallergens is now being produced based on the detailed knowledge of the tertiary structures of the allergens and of the T-cell and B-cell epitopes. The modifications have been made to change the topography of the allergens while retaining a stable, folding structure. In the case of Bet v 1, tertiary structures of hypoallergens have been determined. Structurally modeled hypoallergens have been produced for pollen, venom, food, and latex allergens, with promising characteristics from preclinical studies.

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A Hypoallergenic Derivative of the Major Allergen of the Dust Mite <i>Lepidoglyphus destructor</i>, Lep d 2.6Cys, Induces Less IgE Reactivity and Cellular Response in the Skin than Recombinant Lep d 2

Cited by 9 publications

References 38 publications

Recombinant Allergens in Structural Biology, Diagnosis, and Immunotherapy

Recombinant Allergens in Structural Biology, Diagnosis, and Immunotherapy

Modified Recombinant Allergens for Safer Immunotherapy

Genetically engineered vaccines

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