Presentation made during the EISBM workshop, 13-15 June 2012 by Christophe Pison (EISBM).

1. Prediction the outcome of Lung
Transplantation within the COLT cohort
Pr. Christophe Pison
Pr. Antoine Magnan
Pr. Laurent Nicod
Consortium COLT
Consortium SysCLAD
Inserm1055, Grenoble
European Institute for Systems Biology and
Medicine - EISBM
CHU Grenoble
Univ. J. Fourier

2. Outline
§ Scope and limitations to success in Lung Transplantation (LT)
§ Chronic Lung Allograft Dysfunction (CLAD)
§ Biomarkers in transplantation: why do we fail?
§ From COLT to SysCLAD
§ Perspectives

3. Burden of Respiratory Diseases
§ World, 50.5 M deaths / year, 9.4 millions , 18.7 %
§ 4.30 M, Respiratory infections
§ 2.75 M, COPD
§ 1.6 M, Tuberculosis
§ 0.95 M, Bronchial carcinoma
§ Very poor prognosis
median survival 1-5 years if hypoxemia at rest, no cure
§ Costs in Europe : 100 billions €
§ Indications for Lung Transplantation > 40,000 LTx worldwide
§ COPD
§ Cystic fibrosis
§ Interstitial lung diseases
§ Pulmonary hypertension
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4. Anastomosis Pulmonary veins – left Auricle
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5. QALY - Quality Adjusted Life Years
1
Qualité de vie ajusté sur la survie
123 4 5 6 7 8 9
0,5
1 2 3
Année
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Résultats de la transplantation pulmonaire, S. Quêtant, T. Rochat, C. Pison. RMR 2010; 27:921-938

6. Achilles' tendons in Lung Transplantation
§ Shortage of grafts, Primary Graft Dysfunction
§ Chronic Lung Allograft Dysfunction
-15%, 3 months § BOS in 50% at 5 years
§ different patterns
- 4% / year
§ 30% cause of death > 1 year
§ median survival 1.5 years, if early onset
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7. Survival in Grenoble VI-90 to VI-12
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§ 184 recipients
before XII-2001, n = 70
190 procedures
after XII-2001, n = 114
,8 p: 0.0003 § 7 HL, 57 SL, 120 DL
All § 121 male, 63 females
,6 § 77 COPD
50 CF
,4
40 ILD
18 PH
,2
0
0 12 24 36 48 60 72 84 96 108 120
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8. Chronic Lung Allograft Dysfunction
§ 2 phenotypes BOS / RAS
§ risks factors
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9. Chronic Lung Allograft Dysfunction
§ Risks factors
§ compliance to treatments
§ pollution
Nawrot et al. Thorax 2011;66:748-54 9

10. Biomarkers in transplantation
Why do we fail?
§ 15,000 studies on biomarkers in transplantation, 2 registred..
§ AlloMap®, XDx, 11 informative genes transcripts from PBMC,
a high negative prediction for acute rejection after heart transplantation
Pham et al. N Engl J Med 2010;362:1890-900
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11. Biomarkers in transplantation
Why do we fail?
§ 15,000 studies on biomarkers in transplantation, 2 registred..
§ ImmuKnow®, Cylex,[ATP] blood CD4+
Kowalski et al. Transplantation 2006;82:663-8
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12. Roedder et al. Genome
Medicine 2011;3:37

13. COLT - COhort in Lung Transplantation
COLT
§ 4 May 2012, 11 French centres coordinated by Institut Thorax de Nantes,
Pr. Antoine Magnan : Bichat, Bordeaux, Foch, Grenoble, HEGP, Lyon,
Marie Lannelongue, Marseille, Nantes, Strasbourg, Toulouse
§ 766 candidates to lung transplantation since 2009
§ 532 LT recipients prospectively followed for 5 years
§ Funds PHRC, VLM
§ Karine Botturi, PhD: SOPs, e-CRF, biobank > 30,000 samples,
lung tissues D/R, blood, fresh PBMC, BAL, induced sputum, exhaled air
§ Proteomics, CHU Grenoble, Pr. M. Sève, C. Trocmé PhD
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14. 14

16. 16

17. 17

18. Design- Methods in SysCLAD
§ Prospective cohort > 500 lung transplant recipients, since 2009 in
13 centres COLT and Lausanne, Bruxelles
§ Donors: day 0
§ clinics
§ HLA
§ lung tissue
§ Recipients: before Tx, lung Tx, M6-M12 post LTx
§ clinics, e.CRF
§ Blood: HLA, transcriptomics x 2, proteomics x 2, miRNA x 1,
subpopulations, polymorphism key genes, Toll r..
§ BAL: microbiote, proteomics x 2
§ Outcomes: to predict CLAD @ 3 years by year 1
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19. 21 mois
IE
18 mois
Tech
Mise Purif
au SELDI1 (175 LTR)
biomarqueurs
point
communs SELDI
Mise au iTRAQ1
point
SELDI2 (175 LTR)
iTRAQ2
Rendu biomarqueurs WP3-5
sur 175 LTR
sur 350 LTR
Mise au point dosages
biomarqueurs communs
SELDI iTRAQ (150 LTR) :
modif modèle
Janvier 2013
Avril
Juin 2013
Janvier 2014
Juin 2014
Janvier 2015
Phénotype
Phénotype
Phénotype
Cohorte de caractérisation
220 LTR
350 LTR
500 LTR
Cohorte de validation

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21. Perspectives
§ Strengths
§ COLT > 550 LT recipients by June 2012
§ Systems approach
§ Prediction before function decline
§ Integration D / R
clinical events,
environmental x polymorphisms, omics
§ multilevel / scale signature ?
§ Weakness
§ limited time frame
§ collection data from 13 clinical centres
§ ..
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22. Perspectives
§ Opportunities
§ first attempt to predict CLAD on a personal basis
§ interactions with AirPROM, U-BIOPRED, MeDALL
§ eTRIKS, BioAster
§ Public knowledge tool in Lung transplantation
§ consolidate a sustainable network to improve outcome
predictions in a continuous way for personalized decisions
§ design specific RCTs
§ Use case for other solid organ transplantation
§ Threats
§ bottle necks
§ time..
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23. Acknowledgements
§ Charles Auffray & EISBM colleagues
§ David Koubi & Kevin Deplanche, Finovatis
§ Jean-Pierre & François Boissel, Novadiscovey
§ Dieter Maier, Biomax
§ Karine Botturi, Institut du Thorax, Nantes
§ Candice Trocmé & Michel Sève, Grenoble
§ Colleagues from COLT & Grenoble Lung Transplantation group
§ PHRC, VLM
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