Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma
David JacksonClinical Research Fellow
Department of Respiratory MedicineNational Heart and Lung Institute
Imperial College London
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.
RV
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
Human Model of Rhinovirus Induced Acute Exacerbations of Asthma
Mild Well controlled
Steroid naïve
N = 14
ModeratePoorly controlled
On maintenance inhaled corticosteroids
N = 18
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 = 11 N = 17
Human Model of Rhinovirus Induced Acute Exacerbations of Asthma
Day -15 -14 0 2 3 4 5 7 10 42
RV 16
• Daily spirometry and symptom scores throughout study
• Nasal lavage and Nasosorption at every visit
(PC)20 (PC)20 • BAL• Bronchial brushings • Bronchial biopsies• Bronchosorption
‘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.
Nasosorption
Synthetic Absorptive Matrix (SAM) ‘Leukosorb’ ( Pall Life Sciences)
Bronchosorption Device
Bronchosorption
Sheath SAM advanced Absorbing mucosal lining fluid
RML bronchus RLL bronchus
Kraft M. NEJM 2011
RV
Allergic asthma considered a Th2 mediated disease
Th1 inflammation induced following viral infection in both healthy and asthmatic subjects
Bronchial CCL22 (MDC) correlates with upper and lower respiratory symptoms during RV-infection in asthma
Increased CCL22 (MDC) and CCL17 (TARC) during RV infection with greatest levels in asthma
Kraft M. NEJM 2011
RV
IL-5 is induced by RV in both the upper and lower airway in asthma
Th2 cytokines induced by RV in asthma
IL-13 IL- 4
IL-13 correlates with RV-induced symptoms in asthma
No difference in induction of IFN-gamma (Th1) between asthma and healthy subjects
RV
IL-33Initiator of Type 2 inflammation
Induction by influenza in mice.Chang, Nat Immunol 2011
IL- 33 correlates with Th2 cytokines and chemokines during RV infection in asthma
IL-33 correlates with upper and lower airway symptoms in asthma
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, Pavord NEJM 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
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
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 mAb therapies
• 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
Acknowledgements
• Prof Sebastian Johnston• Dr Trevor Hansel• Belen Trujillo-Torralbo• Jerico del Rosario• Johnston group• Dr Onn Min Kon• Hunt Developments Ltd• Novartis • GSK
Correlation between Upper and Lower Airway Protein Levels in Asthma
Protein
Bronchial D4 Nasal D2
Bronchial D4Nasal D3
Bronchial D4Nasal D4
IL-33 + + -IL-5 +++ + +
IL-13 ++ + -IL-17 + - -IFN-g +++ ++ +IL-15 + +++ -I-TAC - ++ +IP-10 - ++ -IL-6 ++ - -IL-8 +++ ++ -
TNFa +++ ++ +TNF R2 - - -MDC + + -TARC - - -
Eotaxin +++ - -Eotaxin-3 - - -RANTES + ++ +++
IL-2 + - -IL-10 + ++ -
MCP-1 + - -MCP-4 + + -
GM-CSF - - -MIP-1a + ++ -MIP-1b ++ ++ -MIP-3a ++ + -
IL-12p40 + + -IL-1b - - -IL-16 ++ ++ -
+, p = <0.05++, p = <0.01 +++, p = <0.001
Lower Respiratory Symptoms
* P <0.05 Mild compared to moderate asthma
Change in PEF
* P <0.05, ** P <0.01 Poorly-controlled compared to well-controlled# P <0.05, Poorly-controlled compared to partially-controlled