Late Phase IL-13 Production Corresponds to the Clinical Late Allergic Response following Birch Pollen Nasal Allergen Challenge

N. Campion¹; S. Villazala-Merino¹; R. Thwaites²; V. Stanek¹; K. Helen³; E. Pertsinidou⁴; M. Zghaebi¹; J. Toth¹; R. Fröschl¹; G. Katharina¹; S. Sven¹; R. Ristl¹; I. Scott³; S. Cohen³; M. Molin⁴; M. Focke-Tejkl¹; T. Hansel²; R. Valenta¹; J. Eckl-Dorna¹; V. Niederberger-Leppin¹

¹Medical University of Vienna, Wien, Austria; ²Imperial College London, London, United Kingdom; ³AstraZeneca, Milton, United Kingdom; ⁴Thermo Fisher Scientific, Uppsala, Sweden

Background

Nasal allergen provocation studies have shown biphasic nasal responses to provocation where early allergic responses (EAR), within the first hour of allergen exposure, are characterised by rapid release of mast cell mediators (PGD2 and tryptase), complement and D-dimer. In some individuals these are followed after 4-8 hours by secondary “late allergic responses” (LAR) characterised by release of IL-13, IL-5, IL-9 and MMP. However, it is not yet known how these late immune responses are affected by repeated nasal challenge and whether they correspond to nasal symptoms and obstruction in the late phase. In this study we set out to characterise the effects of repeated nasal allergen challenge and to scrutinise the immunological and clinical nasal responses in the LAR.

Method

30 eligible birch-allergic patients were recruited into this double blinded, randomised placebo-controlled trial (birch pollen extract: n=20, placebo: n=10). Nasal challenge with birch extract was performed on 3 consecutive days and 24 hour nasal sampling time courses took place on provocation days 1 and 3. Before, during and after nasal provocation; nasal secretions, total nasal symptom scores (TNSS), visual analogue scales (VAS) and peak nasal inspiratory flows (PNIF) were collected to assess clinical responses. A panel of 33 cytokines was measured in nasal secretions.

Results

All 30 participants completed the study. Patients provoked with birch all showed significant drops in nasal airflow and rises in symptom scores. All patients challenged with birch showed significant increases in tryptase and sST2 in comparison to placebo in the EAR. Some cytokine responses were caused by repeated sampling (eotaxin/CCL11, IL-16) displaying rising concentrations in both placebo and birch challenged patients. 8/20 birch provoked patients displayed significant IL-13 responses in the LAR after nasal challenge. These patients were also the only ones that showed a significant drop in nasal airflow and significant rises of Th2 cytokines as well as IL-6, sST2, EDN and TSLP in the LAR.

Conclusion

Patients with significant IL-13 responses in the LAR were the only patients to display significant clinical and cytokine responses in this phase. Nasal sampling alone has an influence on cytokine concentrations.