Download WAC Systems Biology in Allergy and Asthma 12-7

December 4, 2011
Systems Biology in Allergy and Asthma
Lanny J. Rosenwasser, M.D.
Dee Lyons/Missouri Endowed Chair in Immunology Research
Professor of Pediatrics
Allergy-Immunology Division
Childrens Mercy Hospital
Kansas City, Missouri
Professor of Pediatrics, Medicine and Basic Science
University of Missouri Kansas City School of Medicine
Disclosure Statement
Lanny J. Rosenwasser, MD
• RESEARCH STUDIES
Alcon, A-Z, GlaxoSmithKline, Genentech, Novartis
MBBH/MacArthur Foundation, National Institutes
of Health
• CONSULTANT
Alcon, , A-Z, Genentech, GlaxoSmithKline,
Novartis, Regeneron, Sanofi-Aventis
• SPEAKERS’ BUREAU
Alcon, A-Z, Genentech, Novartis
Learning Objectives
•Understand the nature of Systems Biology
•Examine the complex nature of Immune Response
in Allergy and Asthma
•Understand the applications of Systems Biology to
Allergic Responses
Definitions
Systems Biology – Integrated basis for
functionality of an Organism
Immune Responses – Symphonies of Molecular
and Cellular Mechanisms with each component
generating a coordinated effective response
Analogies - Multiple
Analogies of Complex Disease Process
•Symphony
•Airplane
•Junkyard
•Radio
Modeling and Simulation at Molecular Scale
• Informatics – Software driven
• Modeling of Signaling and Receptor
Activity
• Modeling of Cellular Behavior and
Interactions
Large Scale Data Acquisition Technologies
• Cell and Molecular Biology
• Proteomics, Genomics
• Immunology Wet Lab
Molecular Biological Tools
• Gene and MiRNA Expression
• Transcript Profiling
• Next Generation Sequencing
• RNA; Screening
• Assay Design
• Applications
Interactional Measures
•
•
•
•
•
•
Network Models
2 Hybrid Screens
Mass Spec
Proteomics
Array Protein Assays
Flow Cytometry
Characteristics of Asthma
•
•
•
•
Narrowing of the airways
Airway obstruction
Airway inflammation
Increased airway responsiveness
NHLBI, NAEPP, 1997.
Environmental factors
Th-2/Th-1
cytokines – eg
IL-13, TNF
Environmental factors and
Inflammatory products
Dendritic cell
B lymphocyte
T lymphocyte
IgE
IL-3, IL-5
GM-CSF
IL-3, IL-4,
IL-13, IL-9
TNF
Mast cell
Airway Effects
Bronchospam
Acute Inflammation
Persistent Inflammation
Remodeling
Initiation
(myo) fibroblasts
Eosinophil
Amplification
Airway microenvironment
mucus
Propagation
Smooth muscle
Blood vessels
Neutrophil
Acute Inflammation
Proinflammatory mediators
DRAFT
Persistent inflammation
and development of
remodeling
www.nhlbi.nih.gov/guidelines/asthma/epr3/
Complexity of Asthma
• Several orders of magnitude more
complex
• Microbiome, Proteome, Transcriptome,
Genome
• Tissues, Organs, Whole Body, Brain
• Third and Fourth Dimensions
Stepwise Approach for Managing
Asthma
in Patients Aged ≥12 Years
Persistent Asthma: Daily Medication
Intermittent
Asthma
Consult with asthma specialist if Step 4 care or higher is required.
Consider consultation at Step 3.
Step 6
Step 5
Step 4
Step 3
Step 2
Step 1
Preferred:
SABA PRN
Preferred:
Low-dose ICS (A)
Alternative:
Cromolyn (A),
LTRA (A),
Nedocromil (A),
or
Theophylline (B)
Preferred:
Low-dose ICS +
LABA (A)
OR
Medium-dose ICS
(A)
Alternative:
Low-dose ICS +
either LTRA (A),
Theophylline (B),
or Zileuton (D)
Preferred:
Medium-dose
ICS + LABA (B)
Alternative:
Medium-dose
ICS +
either
LTRA (B),
Theophylline (B),
or Zileuton (D)
Preferred:
High-dose ICS +
LABA (B)
AND
Consider
Omalizumab
for Patients
Who Have
Allergies (B)
Preferred:
High-dose ICS +
LABA + Oral
Corticosteroid
AND
Consider
Omalizumab for
Patients Who
Have Allergies
Each Step: Patient education, environmental control, and management of comorbidities
Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma
Quick-Relief Medication for All Patients
• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at
20-minute intervals as needed. Short course of systemic oral corticosteroids may be needed
• Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control
and the need to step up treatment
ICS = inhaled corticosteroids; LABA = long-acting β2-agonist; LTRA = leukotriene receptor antagonist.
Adapted from National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). U.S.
Department of Health and Human Services. Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf. Accessed August 29, 2007.
Step Up If
Needed
(first, check
adherence,
environmental
control, and
comorbid
conditions)
Assess
Control
Step Down If
Possible
(and asthma is
well controlled at
least 3 months)
Anti IgE
• Targets IgE, FCeRI
• Rhu Mab - E25 - Omalizumab,
Xolair
• Reduces Free IgE (allergen specific)
• Reduces Eos (sputum, BAL, blood)
• Reduces FCeRI and FCeRII
expression
• Efficacy - Asthma, AR
Biotherapeutic Targets in Immune
Allergic Disorders,
Anti-IgE
Innate Immunity Targets
IL-1, TNF, IL-6
TLR, Adhesion Molecules
IFN Modulation
Chemokines
Acquired ImmunityTargets
Th2, Th17 Cytokines
IL-2, 4,5,9,13,17,25,33
Cellular
DC, T, B
Other Targets
TSLP
Adipokines
Growth and Differentiation Factors
IL-1 family members – Chr. 2q13
New Name
Other Name
IL-1F1
IL-1F2
IL-1F3
IL-1F4
IL-1F5
IL-1F6
IL-1F7
IL-1F8
IL-1F9
IL-1F10
IL-1F11
IL-1α
IL-1β
IL-1Ra
IL-18
FIL1δ
FIL-1ε
IL-37
IL-1H2
IL-1ε
IL1HУ2
IL-33
Property
Agonist
Agonist
Receptor antagonist
Agonist
Anti-inflammatory
Agonist
Anti-inflammatory
Agonist
Agonist
Receptor antagonist
Agonist
Extended IL-1 Family
•
•
•
•
(Caspase 1 Dependent)
IL-18 – shared receptor and genetics (IL-18bp)
IL-32 – TNF inducer
IL-33 – Ligand for ST2 Induces TH2 Cytokines
IL-37 – Downregulation of IL-1 family
activities
IL-17 Family
• 20-30 кd
• IL-17A, IL-17F – profibrotic activate
chemokines (IL-8) and IL-6
• IL-17E – IL-25
• IL-25 associated with eosinophilia, airways
hyperresponsiveness
• Genetics of IL-17 family linked to asthma
Key Central
Role of IL-5 in
Asthma
J ALLERGY IMMUNOL 2010 APR
Anti-IL-5 in Human Asthma:
Reduction in Exacerbations
Haldar P et al. New Engl J Med 2009;360:973
Nair P et al. New Engl J Med 2009;360:985
• Severe (CCS-dependent)
asthma
• Sputum eosinophilia required
for enrollment
• No improvement in FEV1,
control, symptoms
Anti-IL-5 in Human Asthma:
Haldar P et al. New Engl J Med 2009;360:973
Nair P et al. New Engl J Med 2009;360:985
Comparison of High Affinity vs. Low Affinity
IgE Receptor
(One log difference in binding)
Effector Cells of
Allergy/Asthma
-Mast Cells
-Basophils
Antigen Presenting Cells
(Modified from Novak, et at. JACI 2003)
CD23a
-B cells
CD23b
-Antigen Presenting Cells
CD 23 as a Target for Therapy
• FCe RII
• 45 KD C-type Lectin
• Type 2 Protein
• Expressed - B-cells, APC, DC
Airway Smooth Muscle
FCER2 – Pleiotropic Effects
FCER2
SNP
G9782a12
G9782a19
G9782a26
G9782a5
G9782a8
Allele
[T/G]
[T/C]
[C/T]
[C/T]
[C/A]
Forest
Haplotype
TTCCC
TCTCA
GTCTA
Phenotype
BD % Change
BD Extremes
Steroid Extremes
Frequency
P-Value
0.06
0.03
0.05
0.05
0.13
0.02
CAMP
Haplotype
GTCTA
GTCTA
GTCTA
TCTTA
TTCCC
Phenotype
BD % Change
BD % Change 1 yr
BD % Change 4 yr
Steroid % Ch. 1 yr
Steroid % Ch. 4 yr
Frequency
P-Value
0.03
0.01
0.02
0.04
0.03
0.15
0.08
0.08
0.04
0.07
Global P value for Steroid % Change 1 yr = 0.001
% with Haplotype
FCER2 – GCTTA Haplotype
50
45
40
35
30
25
20
15
10
5
0
Yes
No
Hospitalizations
ER Visits
p = 0.0001 (Hosp) and 0.01 (ER)
CD23 GENETIC
POLYMORPHISM
AA seq
position
62
Nucleotide
Variant
C to T
Allele
Frequency AA Change
C 0.75 Arginine to
T 0.25 Tryptophan
Genotype of CD23 R62W in Genomic DNA (NT_011145)
3771
Nci I
| 3785
3800
aagagagggctgcccggaacggtatgaagg
3771
|3785
3800
aagagagggctgcctggaacggtatgaagg
ttctctcccgacgggccttgccatacttcc
Agr
Ttctctcccgacggaccttgccatacttcc
trp
393bp
210bp
183bp
R W
Homo
Wild type
Hetero
Kijimoto-Ochiai S., 2002
Tantisera et al JACI,120,1285,2007
Allergy - 2030
• Systems Biology Approach to Allergic Cascades
• Biotherapeutics
• Pharmacogenetic Profiling
• Early Intervention
Systems Medicine
•
•
•
•
Predictive
Preventive
Pharmacologically Effective
Personalized
Challenges for the Future in
Complex Genetic Disease
Translational Research
• Robust Biomarkers
• Phenotype Analysis
Phenotype/Genotype Association
• Diagnostic/Pathologic Visualization
(Nanomedicine)
• Informatics Modeling
References
Ronald N. Germain et al. Systems Biology in
Immunology – A Computational Modeling
Perspective. Annu Rev Immunol. 2011 29: 537-585
David J. Weatherall . Systems Biology and Red
Cells, N ENGL J MED. 2011 364; 375-77.
Sydney Brenner. Sequence and consequences. Phil.
Trans. R. Soc. B 2010 365,207-212.
Acknowledgments
Children’s Mercy Hospital & Clinics
Jianfeng Meng
Marcia A. Chan
Brianna May
Nicole Gigliotti
Sharrion Russell