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
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.
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
Human Model of Rhinovirus Induced Acute
Exacerbations of Asthma
Healthy
N = 14
Mild
Well controlled
Steroid naïve
N = 14
Moderate
Poorly controlled
On maintenance inhaled
corticosteroids
N = 18
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
(PC)20
(PC)20
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•
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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
‘Nasosorption’ and ‘Bronchosorption’:
A new technique for measuring nasal and bronchial
mucosal lining fluid.
•
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•
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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
RML bronchus
Sheath
RLL bronchus
SAM advanced
Absorbing mucosal lining fluid
RV
Allergic asthma
considered a Th2
mediated disease
Th1 inflammation
induced following viral
infection in both
healthy and asthmatic
subjects
Kraft M. NEJM 2011
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
RV
Kraft M. NEJM 2011
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
IL-33
RV
Initiator 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
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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 D4
Nasal D3
Bronchial D4
Nasal 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
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+, p = <0.05
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+++, 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