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Identification of Adjuvants that Enhance the Therapeutic Antibody Response to Host IgE
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. (Hellman)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. Hellman.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Immunology. (Hellman)
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2004 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 22, no 21-22, 2873-2880 p.Article in journal (Refereed) Published
Abstract [en]

In the development of a novel vaccine against atopic allergies, we have screened for adjuvants that enhance the therapeutic antibody response against self immunoglobulin E (IgE). The response against self IgE is induced by administration of a vaccine antigen, which contains both self and non-self IgE regions, together with an adjuvant. We evaluated five commonly used adjuvants; Freund's, aluminium hydroxide, ISCOMs, Montanide ISA 51 and Montanide ISA 720, and found that the mineral oil-based adjuvants; Montanide ISA 51 and Freund's induced at least 5-10-fold higher anti-self IgE titers than any of the other candidates. However, with one exception, Alum, the immune responses against the carrier, i.e. the non-self regions, were similar for all adjuvants, indicating that the ability to induce responses against self and non-self antigens differ among adjuvants. The responses against non-self IgE were more than 50-fold higher than antibody responses against self IgE in both the Freund's and Montanide 51-administered animals, indicating that the response against self molecules is markedly inhibited by tolerance-inducing mechanisms. Co-administration of Montanide ISA 51 with immuno-stimulatory substances from bacteria; muramyldipeptide (MDP), monophosphoryl-lipid A (MPL) or a formyl-methionine-containing tripeptide (fMLP), did not elevate the anti-self IgE response. Hence, adjuvants based on pure mineral oil without additional immuno-stimulatory substances appear to be the best adjuvant candidates in therapeutic vaccines aimed at regulating the in vivo levels of self-proteins.

Place, publisher, year, edition, pages
2004. Vol. 22, no 21-22, 2873-2880 p.
Keyword [en]
Acetylmuramyl-Alanyl-Isoglutamine/pharmacology, Adjuvants; Immunologic/*pharmacology, Aluminum Hydroxide/pharmacology, Animals, Autoantibodies/analysis/biosynthesis, Autoantigens/immunology, Enzyme-Linked Immunosorbent Assay, Female, Hypersensitivity; Immediate/immunology, Immunization Schedule, Immunization; Secondary, Immunoglobulin E/analysis/*biosynthesis/*immunology, Lipid A/pharmacology, Mineral Oil/pharmacology, Opossums/immunology, Plant Oils/pharmacology, Rats, Rats; Wistar
National Category
Engineering and Technology Natural Sciences
URN: urn:nbn:se:uu:diva-91729DOI: 10.1016/j.vaccine.2003.12.029PubMedID: 15246623OAI: oai:DiVA.org:uu-91729DiVA: diva2:164557
Available from: 2004-04-28 Created: 2004-04-28 Last updated: 2013-05-16Bibliographically approved
In thesis
1. More or Less IgE: Therapeutic Vaccines, Adjuvants and Genes and Their Effect on IgE Levels
Open this publication in new window or tab >>More or Less IgE: Therapeutic Vaccines, Adjuvants and Genes and Their Effect on IgE Levels
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Immunoglobulin E (IgE) is an important mediator in atopic allergies. This thesis describes the development of a therapeutic vaccine against IgE and its effects in rats and dogs. The development of an assay to determine IgE levels in dogs, and the finding of a chromosome region in rats that affects IgE levels are also reported.

The vaccine is a chimeric molecule consisting of the constant domains Cε2, Cε3 and Cε4 from IgE. The target domain of the vaccine is the Cε3 domain in the recipient species, which is the domain directly involved in receptor binding, while the flanking regions, Cε2 and Cε4, are from a distantly related mammal. In rats, the vaccine induced an immune response against circulating IgE, which decreased IgE levels by 90% and substantially reduced their allergic symptoms. Further, the effects of adjuvants in rats and dogs were evaluated, and when co-administered with the vaccine certain adjuvants were shown to increase the immune response against IgE. Mineral-oils were the most potent adjuvants in inducing a response against IgE, but metabolizable oils spiked with immunostimulatory substances were also efficient.

It was also shown that the therapeutic vaccine could induce a decrease in IgE levels in adult dogs, even though their initial levels were exceptionally high compared with humans. The IgE levels in 76 dogs ranged between 1 and 41 μg/ml while humans normally have around 150 ng/ml. However, the high IgE levels did not correlate to any specific breed, nor did they distinguish between dogs that were diagnosed as healthy and those suffering from atopic eczema, autoimmunity or skin parasites.

Regulation of total IgE levels probably involves many genes. In the final phase of the study, one candidate locus known to be involved in arthritis susceptibility in rats was investigated, and was found also to affect IgE levels.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 61 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 975
Cell and molecular biology, IgE, Immunoglobulin, Atopic allergy, Vaccine, Adjuvant, Dog, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-4254 (URN)91-554-5959-5 (ISBN)
Public defence
2004-05-19, C8:305, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2004-04-28 Created: 2004-04-28Bibliographically approved

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