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Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma David Jackson Clinical Research Fellow Department of Respiratory Medicine National.

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Presentation on theme: "Rhinovirus Induces Th2 cytokines and chemokines in the Airways in Asthma David Jackson Clinical Research Fellow Department of Respiratory Medicine National."— Presentation transcript:

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 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

4 Human Model of Rhinovirus Induced Acute Exacerbations of Asthma Mild Well controlled Steroid naïve N = 14 Moderate Poorly 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 = 17

5 Human Model of Rhinovirus Induced Acute Exacerbations of Asthma Day RV 16 Daily spirometry and symptom scores throughout study Nasal lavage and Nasosorption at every visit (PC) 20 BAL Bronchial brushings Bronchial biopsies Bronchosorption

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 SheathSAM advancedAbsorbing mucosal lining fluid RML bronchusRLL bronchus

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

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 Kraft M. NEJM 2011 RV

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-13IL- 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 RV IL-33 Initiator of Type 2 inflammation Induction by influenza in mice. Chang, Nat Immunol 2011

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, 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

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 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

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 Protein Bronchial D4 Nasal D2 Bronchial D4 Nasal D3 Bronchial D4 Nasal D4 IL IL IL IL IFN-g IL I-TAC -+++ IP IL IL TNFa TNF R2 --- MDC ++- TARC --- Eotaxin Eotaxin RANTES IL IL MCP MCP GM-CSF --- MIP-1a +++- MIP-1b ++ - MIP-3a +++- IL-12p IL-1b --- IL , p = < , p = < , 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


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