Elsevier

The Lancet

Volume 360, Issue 9326, 6 July 2002, Pages 47-53
The Lancet

Mechanisms of Disease
Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)09332-7Get rights and content

Summary

Background

Some patients with asthma who are allergic to cats and are injected intradermally with short, overlapping, T-cell peptides derived from Fel d 1 develop late asthmatic reactions to the peptides, which are associated with a reduction in late-phase skin reactions induced by whole allergens and bronchial hyporesponsiveness to the peptides on the second injection. We aimed to ascertain the effect of multiple injections on the magnitude of the early and late phase skin reactions to intact allergens.

Methods

After a 9-week run-in period, we randomly assigned patients with asthma and allergies to cats to receive either Fel d 1 peptides (90 μg in increasing divided doses) or placebo. The primary outcome was late-phase cutaneous reactions to whole cat dander. Outcomes were measured at baseline, 4–8 weeks, and 3–9 months. Analysis was by intention to treat.

Findings

16 patients were randomly assigned to the peptides, and eight to placebo. All patients completed the course of injections. Four of the 16 patients on Fel d 1 peptides had initial late asthmatic reactions, but could be desensitised to the higher dose of peptide. Patients in the peptide group but not the placebo group had a significant reduction in the size of their late reaction to whole cat dander between baseline and both follow-ups, but the difference between groups was not significant (first follow-up, difference −422·8 mm2 [95% Cl −1115·0 to 269·4], p=0·43; second follow-up −1180·8 mm2 [−2216·8 to −144·8], p=0·058). The size of the late reaction to Fel d 1 significantly differed between treatment groups at both follow-ups. At second follow-up, the size of the early reaction to Fel D 1, but not to whole cat dander was significantly reduced in those on peptides compared with those on placebo. The concentration of interferon γ and of interleukin 4 and 13, and the amount of proliferation, significantly decreased between baseline and second follow-up, and the concentration of interleukin 10 was significantly higher in patients on peptides, however, none of these values differed significantly between groups. Patients on peptides had a significantly greater decrease in the concentration of interferon γ and interleukin 13, and in the amount of proliferation between baseline and first follow-up than did those on placebo.

Interpretation

Several, short, overlapping Fel d 1 T-cell peptides have potential in treatment of cat allergy.

Introduction

Unpredictable anaphylactic reactions mediated by IgE restrict the usefulness of conventional immunotherapy specific to whole allergens for treatment of atopic allergic disease. Tolerance of fel d 1 by peripheral T cells can be induced in both naive and primed mice by subcutaneous injection of peptides from this major cat allergen.1 Since short peptides derived from the allergen inhibit T-cell function but have restricted ability to cause anaphylaxis owing to loss of three dimensional B cell epitopes, these peptides could be effective as therapeutic vaccines. Accordingly, Norman and colleagues2 and others3, 4, 5 attempted to treat patients allergic to cats by subcutaneous injection of two peptides (IPC1 and IPC2) that spanned a large proportion of chain 1 of Fel d 1. In some studies,2, 3, 4 IPC1 and IPC2 were effective at high doses, but administration of these peptides was associated with allergic symptoms that arose between 10 min and 6 h after injections. Because of the length of this peptide (27 aminoacids), the immediate reactions induced by IPC1 and IPC2 may have been the result of cross linking of IgE. Thus, we synthesised three peptides derived from chain 1 of Fel d 1. The peptides were small (16–17 residues) so that they could be presented to T cells without antigen processing and so that they would be unlikely to cross link allergen-specific IgE. At first, we were interested in the late (6 h) reactions described by Norman and colleagues,2 which we postulated were mediated by T cells. Nine of 40 patients with asthma and allergies to cats who were injected with these peptides developed a late asthmatic reaction, which was dependent on T cells and restricted to specific HLA haplotypes, without first developing an early response dependent on IgE or mast cells.6

We then prepared 12 short overlapping peptides derived from Fel d 1, which spanned most of chain 1 and chain 2 and presumably bind to the many MHC restriction elements present in an outbred population.7 The 12 peptides provoked late asthmatic reactions in a dosedependent fashion, with 50% of patients developing a reaction at the highest dose. However a second injection was associated with an attenuation of this peptide-specific hyper-responsiveness, with up to 40 weeks needed for return to baseline values. The cutaneous late-phase reaction to whole cat dander was also inhibited, as were proliferation of peripheral blood mononuclear cells induced by peptide and whole allergens and production of Th2 (interleukin 4 and 13) and Th1 (interferon γ) cytokines in cultures. Therefore a single injection of allergen-derived peptides induced tolerance to subsequent peptide injection in the target organ (the lung), reduced late-phase cutaneous responsiveness to whole allergen, and changed the reactivity of T cells in vitro.

In this placebo-controlled, double-blind study, we aimed to ascertain whether individuals who are allergic to cats can tolerate increasing, divided doses of multiple, short, peptides derived from Fel d 1 and whether this tolerance inhibits the early and late-phase allergic reactions induced by whole cat dander. We also aimed to determine whether late allergic reactions induced by peptides were associated with the subsequent change in these established clinical surrogate markers of allergy.8, 9, 10 Other outcomes included the allergen inhalation PD20, production of Th1/Th2 and regulatory cytokines by blood mononuclear cells, and tolerance of cats.

Section snippets

Patients

Patients were enrolled by an investigator (WLGO) and the study nurse, and allocated to receive either active or placebo treatment by a random allocation sequence generated by the study statistician at the start of the study. This sequence was held by an independent investigator who dispensed the study drugs.

Patients in the study group received 5 μg, 10 μg, 25 μg, and 50 μg (total dose 90 μg) peptide at 3–4 day intervals over 2 weeks and were observed for 6 h after each injection. Individuals

Results

The table shows patients' baseline characteristics. The active and placebo groups were well matched for sex, age, FEV1, PC20 methacholine, cat radio-allergo-sorbent test, and blood eosinophil counts. About half the patients in each group were taking inhaled corticosteroids. Six of eight in the placebo group, and 14 of 16 in the active treatment group had a positive skin test to three or more allergens. 20 patients completed the study; the remaining four (two active, two placebo) completed the

Discussion

Our results show that treatment with a desensitising vaccine (based on many short, overlapping, HLA-binding, T-cell peptides derived from Fel d 1) inhibited early and late phase allergic reactions to whole allergens and modulated proliferation and production of interleukin 4, 10, and 13, and of interferon γ by peripheral blood mononuclear cells. By contrast with the results of our previous study,7 in which we used a single dose, our findings show that multiple dosing with peptides inhibits

GLOSSARY

activation-induced cell death
Apoptosis induced in lymphocytes following activation through the antigen receptor.
early and late phase allergic reactions
Allergic reactions provoked in vivo by allergen challenge (usually of the nose, skin, eyes, or by inhalation). The reactions are often biphasic with an early (mast cell/histamine) phase arising within minutes and a late (inflammatory cell) phase arising 3–9 h later.
fel d 1
Cat (Felis domesticus) allergen 1.

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