Novel treatment strategies and regulation of IgE-mediated allergic disease
Author: Thunberg, Sarah
Date: 2008-03-07
Location: Thorax aula, byggnad N2, ingång B, plan U1, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
View/ Open:
thesis.pdf (799.9Kb)
Abstract
Allergic symptoms such as rhinoconjunctivitis, asthma or gastrointestinal
symptoms, triggered by inhaled or ingested allergens cross-linking
allergen-specific IgE on mast cells or basophils, are defined as
IgE-mediated allergy. The major allergens from birch pollen (Bet v 1) and
cat dander (Fel d 1) are two common allergens eliciting allergic disease.
Allergen-specific immunotherapy (SIT) is the only curative treatment for
IgE-mediated allergy. It is long-lasting and involves repeated injections
of crude allergen extracts. Successful SIT modifies a number of
allergen-associated immunological responses. SIT has been shown to induce
IL-10 producing regulatory T-cells (Treg), allergen-specific T- and
B-cell anergy as well as blocking antibodies. Although effective, SIT is
associated with a risk for treatment side effects. This has led to the
development of novel treatment strategies, such as modified recombinant
allergens with reduced allergenicity (hypoallergens) and new means of
antigen delivery. The general aim of this thesis is to investigate
regulation of allergic immune responses and how novel strategies for SIT
affect those responses.
The first article describes an eight injection short-course SIT study with Bet v 1 hypoallergens; where 27 birch pollen allergic patients participated. The major findings were that SIT with genetically modified Bet v 1 hypoallergens induced allergen-specific neutralizing antibodies and reduced immediate skin reactivity as well as the number of IL-5 and IL-13 producing cells. Even though rBet v 1 hypoallergen treatment exhibited typical immunological features of successful allergen-specific immunotherapy, there was no increase in the number of IL-10 producing cells after treatment. In the second study we therefore decided to evaluate the role of the suppressive cytokines IL-10 and TGFb as well as natural FOXP3+ Treg cells in immune-regulation of allergic immune responses. We found that unlike Treg cells from non-allergic controls, Treg cells from birch pollen-allergic patients displayed an impaired ability to suppress birch-pollen stimulated effector cells. Neutralization of IL-10 in CD4+CD25+ Treg cell and CD4+CD25- effector cell co-cultures induced a significant increase of TNFa secretion, suggesting that IL-10 and TNFa may have counter-acting properties in the periphery, where IL-10 promotes tolerance and suppression by Treg cells and TNFa promotes inflammatory responses.
In the third and fourth article, recombinant (r) Fel d 1 was coupled to the novel adjuvant carbohydrate based particles (CBPs) and investigated in a mouse model sensitized to Fel d 1. Pre-treatment with CBP-rFel d 1 was able to induce antigen-specific T-cell tolerance and shift immunoglobulin production from an IgE to an IgG2a type of response. Antigen-coupled CBPs also demonstrated improved antigen depot-effects with prolonged antigen-exposure, when compared to the most commonly used adjuvant in vaccine preparations for humans; aluminum hydroxide. Furthermore, CBP-rFel d 1 was tested in a treatment protocol for SIT, where it was able to modulate the allergic immune response in rFel d 1 sensitized mice without adverse effects. Thus, CBPs ability to promote induction of potent immune responses and to deliver allergens without risk of systemic allergen spreading are beneficial properties of an adjuvant aimed to be used in allergen-specific immunotherapy. Possibly, CBPs coupled to infectious or auto-immune antigens could be applied as an adjuvant to prevent other types of diseases.
In conclusion, the work presented in this thesis has shed new light on in vivo function of two conceptually different approaches to improve allergen-specific immunotherapy. The thesis has also contributed to increased understanding regarding regulation of allergic immune-responses, thus providing a basis for further research.
The first article describes an eight injection short-course SIT study with Bet v 1 hypoallergens; where 27 birch pollen allergic patients participated. The major findings were that SIT with genetically modified Bet v 1 hypoallergens induced allergen-specific neutralizing antibodies and reduced immediate skin reactivity as well as the number of IL-5 and IL-13 producing cells. Even though rBet v 1 hypoallergen treatment exhibited typical immunological features of successful allergen-specific immunotherapy, there was no increase in the number of IL-10 producing cells after treatment. In the second study we therefore decided to evaluate the role of the suppressive cytokines IL-10 and TGFb as well as natural FOXP3+ Treg cells in immune-regulation of allergic immune responses. We found that unlike Treg cells from non-allergic controls, Treg cells from birch pollen-allergic patients displayed an impaired ability to suppress birch-pollen stimulated effector cells. Neutralization of IL-10 in CD4+CD25+ Treg cell and CD4+CD25- effector cell co-cultures induced a significant increase of TNFa secretion, suggesting that IL-10 and TNFa may have counter-acting properties in the periphery, where IL-10 promotes tolerance and suppression by Treg cells and TNFa promotes inflammatory responses.
In the third and fourth article, recombinant (r) Fel d 1 was coupled to the novel adjuvant carbohydrate based particles (CBPs) and investigated in a mouse model sensitized to Fel d 1. Pre-treatment with CBP-rFel d 1 was able to induce antigen-specific T-cell tolerance and shift immunoglobulin production from an IgE to an IgG2a type of response. Antigen-coupled CBPs also demonstrated improved antigen depot-effects with prolonged antigen-exposure, when compared to the most commonly used adjuvant in vaccine preparations for humans; aluminum hydroxide. Furthermore, CBP-rFel d 1 was tested in a treatment protocol for SIT, where it was able to modulate the allergic immune response in rFel d 1 sensitized mice without adverse effects. Thus, CBPs ability to promote induction of potent immune responses and to deliver allergens without risk of systemic allergen spreading are beneficial properties of an adjuvant aimed to be used in allergen-specific immunotherapy. Possibly, CBPs coupled to infectious or auto-immune antigens could be applied as an adjuvant to prevent other types of diseases.
In conclusion, the work presented in this thesis has shed new light on in vivo function of two conceptually different approaches to improve allergen-specific immunotherapy. The thesis has also contributed to increased understanding regarding regulation of allergic immune-responses, thus providing a basis for further research.
List of papers:
I. Gafvelin G, Thunberg S, Kronqvist M, Grönlund H, Grönneberg R, Troye-Blomberg M, Akdis M, Fiebig H, Purohit A, Horak F, Reisinger J, Niederberger V, Akdis CA, Cromwell O, Pauli G, Valenta R, van Hage M (2005). "Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1." Int Arch Allergy Immunol 138(1): 59-66.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Thunberg S, Akdis M, Akdis CA, Grönneberg R, Malmström V, Trollmo C, van Hage M, Gafvelin G (2007). "Immune regulation by CD4+CD25+ T cells and interleukin-10 in birch pollen-allergic patients and non-allergic controls." Clin Exp Allergy 37(8): 1127-36.
Fulltext (DOI)
Pubmed
Fulltext (DOI)
III. Thunberg S, Neimert-Andersson T, Cheng Q, Wermeling F, Swedin, L., Dahlén, SE, Bergström U, Arnér E, Scheynius A, Karlsson MCI, Gafvelin G, van Hage M, Grönlund H. (2008). "Pro-longed antigen-exposure with rFel d 1-coupled carbohydrate based particles prevents induction of allergic immune responses". [Submitted]
IV. Neimert-Andersson T, Thunberg S, Swedin L, Dahlén SE, Wiederman U, Jacobsson-Ekman G, Scheynius A, Grönlund H, van Hage M, Gafvelin G (2008). "Carbohydrate-based particles reduce allergic inflammation in a mouse model for cat allergy". [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Gafvelin G, Thunberg S, Kronqvist M, Grönlund H, Grönneberg R, Troye-Blomberg M, Akdis M, Fiebig H, Purohit A, Horak F, Reisinger J, Niederberger V, Akdis CA, Cromwell O, Pauli G, Valenta R, van Hage M (2005). "Cytokine and antibody responses in birch-pollen-allergic patients treated with genetically modified derivatives of the major birch pollen allergen Bet v 1." Int Arch Allergy Immunol 138(1): 59-66.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Thunberg S, Akdis M, Akdis CA, Grönneberg R, Malmström V, Trollmo C, van Hage M, Gafvelin G (2007). "Immune regulation by CD4+CD25+ T cells and interleukin-10 in birch pollen-allergic patients and non-allergic controls." Clin Exp Allergy 37(8): 1127-36.
Fulltext (DOI)
Pubmed
Fulltext (DOI)
III. Thunberg S, Neimert-Andersson T, Cheng Q, Wermeling F, Swedin, L., Dahlén, SE, Bergström U, Arnér E, Scheynius A, Karlsson MCI, Gafvelin G, van Hage M, Grönlund H. (2008). "Pro-longed antigen-exposure with rFel d 1-coupled carbohydrate based particles prevents induction of allergic immune responses". [Submitted]
IV. Neimert-Andersson T, Thunberg S, Swedin L, Dahlén SE, Wiederman U, Jacobsson-Ekman G, Scheynius A, Grönlund H, van Hage M, Gafvelin G (2008). "Carbohydrate-based particles reduce allergic inflammation in a mouse model for cat allergy". [Accepted]
Fulltext (DOI)
Pubmed
View record in Web of Science®
Issue date: 2008-02-15
Rights:
Publication year: 2008
ISBN: 978-91-7357-440-2
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