Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro.

Akdiş, Cezmi A.; Akdiş, Mübeccel; Blesken, Thorsten; Wymann, Daniel; Alkan, Şefik Ş.; Müller, Ulrich; Blaser, Kurt

doi:10.1172/jci118963

Cited by 288 publications

(341 citation statements)

References 63 publications

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“…Clinical studies suggested that immunotherapy exerted its beneficial effect by anergy induction of allergen-specific Th2 cells, or by modulation of the Th2 response toward a Th1 or a regulatory T cell response (11)(12)(13). These observations resulted in various hypotheses on the mechanism of allergen immunotherapy encompassing roles for the dose of Ag (including t 1/2 and number of ligands expressed on the APC), the affinity of the TCR for the MHC-peptide complex, the type of APC (differences in costimulatory molecules and cytokines), and the route of administration (10, 14 -16).…”

Section: The Efficacy Of Immunotherapy In An Experimentalmentioning

confidence: 99%

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

Janssen

Oosterhout

Nijkamp

et al. 2000

The Journal of Immunology

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In the present study, the relation between the efficacy of immunotherapy, and the strength and site of T cell activation during immunotherapy was evaluated. We used a model of allergic asthma in which OVA-sensitized and OVA-challenged mice display increased airway hyperresponsiveness, airway inflammation, and Th2 cytokine production by OVA-specific T cells. In this model, different immunotherapy strategies, including different routes of administration, or treatment with entire OVA or the immunodominant T cell epitope OVA323–339, or treatment with a peptide analogue of OVA323–339 with altered T cell activation capacity were studied. To gain more insight in how immunotherapy affects allergen-specific T cells, the site of Ag-specific T cell activation and the magnitude of the T cell response induced during different immunotherapy strategies were determined using an adoptive transfer model. Our data suggest that amelioration of airway hyperresponsiveness and inflammation is associated with the induction of a strong, synchronized, and systemic T cell response, resulting in a decreased OVA-specific Th2 response. In contrast, deterioration of the disease after immunotherapy is associated with the induction of a weak nonsynchronized T cell response, resulting in the enhancement of the OVA-specific Th2 response after challenge.

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Section: The Efficacy Of Immunotherapy In An Experimentalmentioning

confidence: 99%

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

Janssen

Oosterhout

Nijkamp

et al. 2000

The Journal of Immunology

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“…To investigate whether the Api m (1/2/3) is able to target specific T cells, the allergen-induced proliferative and cytokine responses in PBMC from BV-allergic 3 . In contrast to control animals, the Api m (1/2/ 3) and Api m 1 pretreatment resulted in the inhibition of Api m 1-specific IgE, IgG1 and IgG2a (Fig.…”

Section: Api M (1/2/3) Retains the Ability To Stimulate Human T Cellsmentioning

confidence: 99%

“…Two groups of female C57BL/6 mice (4-6 wk of age, n=6) were immunized s.c. with 100 lg/100 ll of Api m (1/2/3) and Api m 1 in saline 14, 10 and 6 days prior to i.p. immunization with 100 lg/100 ll of Api m 1/Al(OH) 3 . Control mice (n=6) received s.c. injections with saline alone.…”

Section: Induction and Regulation Of Specific Antibodies In Micementioning

confidence: 99%

“…with BV in Al(OH) 3 , three times 0.5 mg/100 mL and three times 5 mg/100 lL bi-weekly. Control animals (n=6) received s.c. injections with saline alone.…”

Section: Induction and Regulation Of Specific Antibodies In Micementioning

confidence: 99%

“…The immune response to bee venom (BV) provides an especially suitable model to study human cellular and molecular mechanisms regulating allergy and normal immunity [2,3]. Phospholipase A 2 (Api m 1) and hyaluronidase (Api m 2) represent major allergens in BV [4,5].…”

Section: Introductionmentioning

confidence: 99%

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Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes

Karamloo¹,

Schmid‐Grendelmeier

Kussebi³

et al. 2005

Eur. J. Immunol.

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Novel approaches for the prevention of allergy are required, because of the inevitably increasing prevalence of allergic diseases during the last 30 years. Here, a recombinant chimeric protein, which comprises the whole amino acid sequences of three bee venom major allergens has been engineered and used in prevention of bee venom sensitization in mice. Phospholipase A 2 (Api m 1), hyaluronidase (Api m 2) and melittin (Api m 3) fragments with overlapping amino acids were assembled in a different order in the Api m (1/2/3) chimeric protein, which preserved entire T cell epitopes, whereas B cell epitopes of all three allergens were abrogated. Accordingly, IgE cross-linking leading to mast cell and basophil mediator release was profoundly reduced in humans. Supporting these findings, the Api m (1/2/3) induced 100 to 1000 times less type-1 skin test reactivity in allergic patients. Treatment of mice with Api m (1/2/3) led to a significant reduction of specific IgE development towards native allergen, representing a protective vaccine effect in vivo. These results demonstrate a novel prototype of a preventive allergy vaccine, which preserves the entire T cell epitope repertoire, but bypasses induction of IgE against native allergen, and side effects related to mast cell/basophil IgE FceRI cross-linking in sensitized individuals.

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Differential regulation of human T cell cytokine patterns and IgE and IgG4 responses by conformational antigen variants

Akdiş¹,

Blesken²,

Wymann³

et al. 1998

Eur. J. Immunol.

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Bee venom phospholipase A2 (PLA) represents the major allergen and antigen in allergic and non-allergic individuals sensitized to bee sting. We have studied specific activation of peripheral T cells by different structural and conformational variants of PLA and secretion of cytokines regulating IgE and IgG4 antibody (Ab) formation. PLA molecules expressing the correctly folded tertiary structure, which show high affinity to membrane phospholipids and were recognized by Ab from bee sting allergic patients, induced high IL-4, IL-5 and IL-13 production in peripheral blood mononuclear cell cultures. In contrast, non-refolded recombinant PLA (rPLA) and reduced and alkylated native PLA (nPLA) induced more IFN-gamma and IL-2 and higher proliferative responses. Differences in proliferation and cytokine patterns among correctly folded and non-refolded PLA resulted from conformation-dependent involvement of different antigen-presenting cell (APC) types. Antigen (Ag)-presenting B cells recognized PLA only in its natural conformation, stimulated Th2 type cytokines and induced IgE Ab. Non-refolded PLA was recognized, processed and presented exclusively by monocytes and induced a Th1 dominant cytokine profile leading to IgG4 production by B cells. The possibility that production of particular cytokine patterns and Ig isotype was influenced by the enzymatic activity of PLA was excluded by using enzymatically inactive H34Q point-mutated, refolded rPLA. These findings demonstrate the decisive role of specific Ag recognition by different APC, depending on structural features, membrane phospholipid binding property and the existence of conformational B cell epitopes, in the differential regulation of memory IgE and IgG4 Ab. Furthermore, they show that a change from IgE-mediated allergy to normal immunity against a major allergen can be induced by rPLA variants that are not recognized by specific Ab and B cells but still carry the T cell epitopes. These features may enable new applications for safer immunotherapy.

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Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro.

Cited by 288 publications

References 63 publications

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

The Efficacy of Immunotherapy in an Experimental Murine Model of Allergic Asthma Is Related to the Strength and Site of T Cell Activation During Immunotherapy

Prevention of allergy by a recombinant multi-allergen vaccine with reduced IgE binding and preserved T cell epitopes

Differential regulation of human T cell cytokine patterns and IgE and IgG4 responses by conformational antigen variants

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