Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma
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Transcript of Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma
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