Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma

1. Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma David Jackson Clinical Research Fellow Department of Respiratory Medicine National Heart and Lung Institute Imperial College London

2. Introduction • Asthma is a chronic condition characterised by reversible airflow obstruction, airway hyper-responsiveness, and airway inflammation • Affects 1 in 12 of the UK population • NHS costs are ~£1bn/yr • Asthma exacerbations are the major cause for morbidity, mortality and healthcare costs in asthma • Respiratory viruses are the most frequent trigger for exacerbations • Rhinovirus identified in the majority of episodes • Johnston BMJ 1995… many studies since.

3. Human Model of Rhinovirus Induced Acute Exacerbations of Asthma • ↑ RV-induced lower airway involvement in mild asthmatics compared to healthy volunteers • ↑symptoms, ↓lung function and ↑AHR. • - Corne, Lancet 2002; Message, PNAS 2008 RV

4. Human Model of Rhinovirus Induced Acute Exacerbations of Asthma Moderate Poorly controlled On maintenance inhaled corticosteroids N = 18 Mild Well controlled Steroid naïve N = 14 Healthy N = 14 Infection confirmed by demonstration of RV16 RNA by RT-PCR in nasal lavage and serum titre of RV-16 specific antibodies ≥ 1:4 on day 42. N = 11 N = 17 N = 11

5. Human Model of Rhinovirus Induced Acute Exacerbations of Asthma (PC)20 (PC)20 • BAL • Bronchial brushings • Bronchial biopsies • Bronchosorption RV 16 Day -15 -14 0 2 3 4 5 7 10 42 • Daily spirometry and symptom scores throughout study • Nasal lavage and Nasosorption at every visit

6. ‘Nasosorption’ and ‘Bronchosorption’:A new technique for measuring nasal and bronchial mucosal lining fluid. • Accurate measurement of proteins in nasal lavage and BAL is extremely difficult. • Variable recovery of saline • Variable dilutions • Many proteins below limits of detection • BAL can lead to bronchospasm in asthmatics • Large proportion of patients complain of a fever following BAL • In paediatrics even nasal lavage considered too invasive and difficult for some age groups.

7. Nasosorption Synthetic Absorptive Matrix (SAM) ‘Leukosorb’ ( Pall Life Sciences)

8. Bronchosorption Device

9. Bronchosorption RML bronchus RLL bronchus Sheath SAM advanced Absorbing mucosal lining fluid

10. Allergic asthma considered a Th2 mediated disease Th1 inflammation induced following viral infection in both healthy and asthmatic subjects RV Kraft M. NEJM 2011

11. Bronchial CCL22 (MDC) correlates with upper and lower respiratory symptoms during RV-infection in asthma

12. Increased CCL22 (MDC) and CCL17 (TARC) during RV infection with greatest levels in asthma

13. RV Kraft M. NEJM 2011

14. IL-5 is induced by RV in both the upper and lower airway in asthma

15. Th2 cytokines induced by RV in asthma IL-13 IL- 4

16. IL-13 correlates with RV-induced symptoms in asthma

17. No difference in induction of IFN-gamma (Th1) between asthma and healthy subjects

18. IL-33 • Initiator of Type 2 inflammation • Induction by influenza in mice. • Chang, Nat Immunol 2011 RV

19. IL- 33 correlates with Th2 cytokines and chemokines during RV infection in asthma

20. IL-33 correlates with upper and lower airway symptoms in asthma

21. Is RV induction of Th2 pathways in asthma clinically relevant? • Mepolizumab (anti-IL-5 mAb) → fewer severe exacerbations in subjects with severe refractory eosinophilic asthma. (RR 0.57; p = 0.02) • Haldar, PavordNEJM 2009 • Lebrikizumab (anti-IL-13 mAb) → rate of exacerbations 60% lower in ‘high-Th2’ subgroup only (p = 0.03). No significant effect on other asthmatics. • Corren, Matthews NEJM 2011

22. Baseline levels of Th2 cytokines predict levels during exacerbation Great potential to use nasosorption in the clinic to identify suitable patients for anti- IL-5 / anti IL-13 drugs

23. Summary • Bronchosorption and nasosorption allows measurement of previously undetectable proteins • Induction of IL-33 and the Th2 pathway by virus in asthma in vivo and relationships to clinical outcomes • provides explanation for effectiveness of anti-IL-5 and anti-IL-13 mAb’s in preventing exacerbations in selected asthmatics • Baseline levels of IL-5 and IL-13 predict magnitude of induction by virus – possibility to identify suitable asthmatics for mAbtherapies • Correlation between upper and lower airway protein levels at baseline and following RV infection in asthma • Asthma is heterogeneous – new treatments needs to be targeted

24. Acknowledgements • Prof Sebastian Johnston • Dr Trevor Hansel • Belen Trujillo-Torralbo • Jerico del Rosario • Johnston group • Dr Onn Min Kon • Hunt Developments Ltd • Novartis • GSK

25. Correlation between Upper and Lower Airway Protein Levels in Asthma +, p= <0.05 ++, p= <0.01 +++, p= <0.001

26. Lower Respiratory Symptoms * P <0.05 Mild compared to moderate asthma

27. Change in PEF * P <0.05, ** P <0.01 Poorly-controlled compared to well-controlled # P <0.05, Poorly-controlled compared to partially-controlled