Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom,☆☆,,★★

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Abstract

Background: Specific immunotherapy with honeybee venom (BV) is highly effective, but allergic side effects can occur during treatment. Immunotherapy with peptides containing major T-cell epitopes of the relevant allergen or allergens provides an alternative strategy without these problems. Objective: The study investigates the immunologic mechanisms and clinical effects of immunotherapy with T-cell epitope peptides of the major BV allergen, the phospholipase A2 (PLA). Methods: Five patients with IgE-mediated systemic allergic reactions to bee stings were treated with a mixture of three T-cell epitope peptides of PLA. Ten patients allergic to BV receiving whole BV immunotherapy served as control subjects. Increasing doses of the peptide mixture, up to a maintenance dose of 100 μg, were administered subcutaneously within 2 months. The patients were then challenged with PLA and 1 week later with a bee sting. The cellular and humoral immune response was measured in vitro. Results: No allergic side effects were caused by the peptide immunotherapy, and all patients tolerated the challenge with PLA without systemic allergic symptoms. Two patients developed mild systemic allergic reactions after the bee sting challenge. After peptide immunotherapy, specific proliferative responses to PLA and the peptides in peripheral blood mononuclear cells were decreased in successfully treated patients. The production of T H2 and T H1 cytokines was inhibited, and B cells were not affected in their capacity to produce specific IgE and IgG4 antibodies. Their levels increased after allergen challenge in favor of IgG4. Conclusions: Immunotherapy of BV allergy with short T-cell peptides of PLA induces epitope-specific anergy in peripheral T cells and changes the specific isotype ratio in a fashion similar to that of conventional immunotherapy in successfully treated patients. (J Allergy Clin Immunol 1998;101:747-54.)

Section snippets

Antigens and reagents

Whole BV for skin tests and BVIT (Pharmalgen) was obtained from ALK (Horsholm, Denmark), and natural (n)PLA was obtained from Boehringer (Mannheim, Germany). Recombinant (r)PLA was expressed and refolded as described previously.15 The three PLA peptides were synthesized by automated solid-phase synthesis, with subsequent high-performance liquid chromatography. For skin testing and PIT, allergens and peptides were dissolved in commercially available diluent (Pharmalgen, ALK). IL-2 was a gift

Clinical course

The five patients (numbers 1, 2, 3, 4, and 5) were subjected to PIT with an equimolar mixture of the three PLA peptides PLA PI, PII, and PIII, each expressing a single T-cell epitope. The results of PIT were compared with those of 10 patients receiving BVIT. The clinical course and the results of the provocation tests in patients receiving PIT are shown in Table III. During PIT, no local or systemic allergic symptoms or any other side effects were caused by the subcutaneously injected peptides

DISCUSSION

In this first study of PIT in BV allergy, we applied an equimolar mixture of three short peptides, each containing a T-cell epitope of the major BV allergen PLA. The total dose of peptides injected corresponded to a 40-times higher amount of PLA than normally applied in BVIT. This was possible because the peptides did not bind IgE antibodies, and the skin sensitivity to the peptides was at least 104 times lower than that to intact PLA. Successful PIT correlated with the induction of specific

Acknowledgements

We thank Dr. Sefik Alkan, Novartis, Basel for his assistance in determination of some cytokines.

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    From aMedical Division, Zieglerspital, Bern; bSwiss Institute of Allergy and Asthma Research (SIAF), Davos; and cInstitute of Immunology and Allergology, Inselspital, Bern.

    ☆☆

    Supported by the Swiss National Science Foundation (grant no. 31.39.177.93).

    Reprint requests: Kurt Blaser, PhD, Swiss Institute of Allergy and Asthma Research (SIAF), CH-7270 Davos, Switzerland.

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