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LUNG CANCER AND
COPD
The two sides of the coin
Manuel G. Cosio
(Padova/Montreal)
LUNG CANCER AND COPD
The two sides of the coin
• An adaptive immune inflammation, and
probably autoimmunity, is important in the
development of COPD.
• Could this inflammation be a factor in the
development of lung cancer in smokers?
T-cell inflammation
in COPD:
Emphysema
Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54
From Lung tissue
CD8+ inflammation in small airways
Normal
Saetta M: Am J Respir Crit Care Med 1998;157:822–826.
COPD
Lung inflammation in smokers
T-cells in the lung are:
•Oligoclonal.
• Activated:
CD4+ express a Th-1 profile
CD8+ express perforin and granzimes.
B-cells: oligoclonal lymphoid follicles
• The inflammatory infiltrate persists after
smoking cessation.
These are signs of antigenic activation
of the adaptive immune system
Majo J, Ghezzo H, Cosio M. Eur Respir J, 2001;17:946-953
Saetta M Di Stefano A, Turato G et al: Am J Resp Crit Care Med;1998, 157: 822
Retamales J et al. Am j Respir Crit Care Med:2001; 164; 469
Adoptive transfer of pathogenic T Cells induce COPD-like Disease.
Inflammation & emphysema
with or without CS exposure
When T cells from cigarette smoke exposed mice are
transferred to mice deprived of Tcells (Rag2-/-) they are able
to induce emphysema even without further exposure to
cigarette smoke.
Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010
The autoimmune mechanism in
COPD:
the “steps” approach.
N Engl J Med 2009;360:2445-54
COPD: EVASION AND PROGRESSION
STEP 1
STEP 2
GOLD 0, I ?
GOLD I, II ?
STEP 3
GOLD III, IV?
innate immunity
Resolution of inflammation:
Regulons
Inhibiting protein translation.
Promoting mRNA decay
tolerance
AUTOIMMUNITY
Adaptive immunity
Tolerance failure.
Genetic
predisposition.
Epigenetics ?
immunity
Immune system in smokers
• Immunosuppressed:
•
•
•
•
•
•
DC presenting and maturation
PMNs and AMs
T-cell anergy
B-cells
Immunoglobulins
Markers and mediators
Martin R. Stämpfli: NATURE Reviews | Immunology; volume 9 | May 2009 | 377
1551 patients with COPD followed for 15 years
1.- Evasion/progression
età e Pk-y GOLD
phenotype?
70
2.- Patient selection for
studies
60
50
40
età
Pky
30
3.-Responses to treatment
4.- Searching for
Biomarkers
20
10
0
Gold4
Gold3
Data from J.M. Marin Trigo
Gold2
Gold1
5.- Understanding
other comorbidities:
cancer
Smoking, immunity, COPD and cancer.
Working Hypothesis.
• Active adaptive immunity is important to defend
against the development of malignancy.
• If normal smokers suppress immunity to avoid
COPD, they would develop more cancers than
smokers with severe COPD, who have very active
adaptive immunity
Lung cancer in COPD
• A cohort of 2588 patients with COPD and without
initial clinical or radiological evidence of lung cancer
was followed for 62±38 months.
• A total of 222 of the 2588 COPD patients developed
lung cancer for an incidence density of 15.8
cases/1000 persons year. The most frequent
histological type was squamous cell carcinoma
(44%).
From Torres, Marin,… Saetta, Cosio, Celli ; unpublished.
GOLD IV 14%
PLATINUM 1.5%
BOLD 3.3%
Gold I: 48% adeno; 39% squam; 9% small cell;3% other
Gold II: 35% adeno; 47% squam; 9% small cell;
Gold III: 29% adeno; 46% squam; 21 small cell;4% other
Cox multivariate regression analysis of factors
that predict lung cancer
Parameter
Age
DLCO<80%
predicted
BMI
GOLD stage
I
II
III
IV
Hazard Ratio
95% CI
p value
1.02
1.00-1.04
0.029
1.76
1.15-2.69
0.009
0.95
0.92-0.99
0.011
3.05
2.06
1.67
Reference
1.41-6.59
1.01-4.18
0.81-3.44
0.005
0.044
0.159
Variables included in the model: age, BMI, pack-year history, smoking status,
GOLD, DLCO<80% and IC/TLC<0.25.
Cancer diagnosis in patients classified according to the DLCO
Subsequent COPD and lung cancer in patients
with autoimmune disease
Standardized incidence ratios (SIRs) ( ratio of observed to
expected)
297,300, patients
18/29 autoimmune diseases associated with COPD: SIR 5.69-3.08
5/29 associated with cancer:
Systemic sclerosis 4.45
Discoid LE 4.24
Poymyositis/dermatomyositis 3.92
K. Hemminki: Eur Respir J 2011; 37: 463–474
Conclusions 1
• Autoimmunity is the most likely mechanism
for the development of severe COPD.
• In order to evade COPD smokers suppress
their immune system.
• Suppression of the immune system could
promote the development of cancer in
smokers.
Conclusions 2
• Smokers in Gold stages I and II (and possibly
0) and a low DLCO are at high risk for the
development of lung cancer.
• These patients should be followed more
carefully and might benefit from screening
programs
STEP I and II
The resolution of the immune response
STEP 1
Resolution of inflammation: Regulons
Inhibiting protein translation.
Promoting mRNA decay
Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54
STEP 2
1551 patients with COPD followed for 15 years
% of lung cancer all cases
8
7
% of lung cancer
6
5
4
Serie1
3
2
1
0
gold1
gold2
gold3
gold4
total cases developing any cancer
gold stage
12
Myeloid- derived suppressor cells
(MDSCs)
% with cancer
10
8
6
4
2
0
M1/M2 Alveolar Macrophages
gold 1
gold 2
gold 3
gold stage
gold 4
Napoli: 105 outpatient cases presenting with lung cancer.
% cancer diagnosed by Gold stages
% of
%
Prof. Serafino Marsico
Dott.ssa Cecilia Calabrese
1551 patients with COPD followed for 15 years
età e Pk-y GOLD
70
60
50
40
età
Pky
30
20
10
0
Gold4
Gold3
Gold2
Gold1
Defining criteria for autoimmune diseases (
Witebsky’s postulates)
• Direct proof: Disease is reproduced in a normal recipient
by direct transfer of autoantibody or T-cell transfer.
• Indirect evidence : Identify offending antigen in
humans and reproduce the disease by experimental
immunization. Isolation of autoantibodies or self-reactive Tcells from the organ.
• Circumstantial evidence: Lymphocytic infiltration of
target organ. Association with a particular MHC (Hla)
haplotype.
Rose Noel and Bona Constantin Immunology Today 1993, 14, 426.
Lambrecht B and Hammad H. Nature Reviews Immunology. 2003, 3, 994
Defining criteria for autoimmune diseases
• Direct proof: Disease is reproduced in a normal recipient
by direct transfer of autoantibody or T-cell transfer.
• Indirect evidence : Identify offending antigen in
humans and reproduce the disease by experimental
immunization. Isolation of autoantibodies or self-reactive Tcells from the organ.
• Circumstantial evidence: Lymphocytic infiltration of
target organ. Association with a particular MHC (Hla)
haplotype.
Defining criteria for autoimmune diseases
• Direct proof: Disease is reproduced in a normal recipient
by direct transfer of autoantibody or T-cell adoptive transfer.
• Indirect evidence : Identify offending antigen in
humans and reproduce the disease by experimental
immunization. Isolation of autoantibodies or self-reactive Tcells from the organ.
• Circumstantial evidence: Lymphocytic infiltration of
target organ. Association with a particular MHC (Hla)
haplotype.
Pathogenic T Cells Capable of Driving COPD-like Disease in Rag22/2 Mice
•T-cells oligoclonal: strongly implicates antigen-specific T-cells
as mediators of disease pathogenesis.
•Transferred T-cells organ specific: only found in LUNG
Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010
Pathogenic T Cells are Capable of Driving COPD-like Disease in Rag22/2 Mice
•Chronic cigarette smoke exposure generates pathogenic T-cells.
•Transfer of these cells into a T-cell deprived animal (Rag2-/-) induces many
of the phenotypic changes associated with COPD.
•These changes, which occur without further exposure to cigarette smoke,
are features indicative of autoimmunity.
Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010
"Eccellenze in pneumologia Interventistica"
La risposta immune nella BPCO.
Una relazione con il cancro di polmone?
Manuel G. Cosio
Marina Saetta.
Napoli 2011
1983
normal
COPD
Pathogenic T Cells Capable of Driving COPD-like Disease in Rag22/2 Mice
•T-cells oligoclonal: strongly implicates antigen-specific T-cells
as mediators of disease pathogenesis.
•Transferred T-cells organ specific: only found in LUNG
Motz. Am J Respir Crit Care Med Vol 181. pp 1223–1233, 2010
Evidence of autoimmunity
The reproduction of the disease in a normal
recipient by T-cell adoptive transfer,
provides direct proof for autoimmunity (in
animal models) and supports the concept of
an autoimmune mechanism in COPD.
Napoli: 105 outpatient cases presenting with lung cancer.
% of cancer diagnosed by Gold stages
%
50
40
30
20
10
0
gold 0 gold1 gold2 gold3 gold4
Prof. Serafino Marsico
Dott.ssa Cecilia Calabrese
The original paradigm
From
BAL
NE
PR3
AZU
elastase
Oxidative stress
MMP
MME
BREAKDOWN OF THE LUNG
Only 20% develop
COPD !! Why??
COPD
Low molecular weight
elastin peptides
Desmosine
Hyroxiproline
normal
COPD
Correlation of alveolar wall
inflammation and emphysema
Saetta M et al. Am Respir Dis 1990;
141 1547-1552
Finkelstein R, Fraser R, Ghezzo H, Cosio M Am J Respr Crit Care Med 1995; 152:1666-1672
Autoimmunity in COPD
“If T-cells are responsible for the lung injury and
progression of COPD, it would be as a response to an
antigenic stimulus originating in the lung induced by
cigarette smoking”.
If that were the case, COPD could be
considered an autoimmune disease triggered
by smoking.”
Majo J, Ghezzo H, Cosio MG. Eur Respir J, 2001; 17: 946-953
STEP I
The innate immune response:
Danger signals and TLRs.
antigens
Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54
regulation
STEP II
The adaptive Immune
response:
local lymphoid tissue,
Dendritic Cells.
Cosio M, Saetta M, Agusti A: N Engl J Med
2009;360:2445-54
STEP III
Autoimmune lung
Injury.
Cosio M, Saetta M, Agusti A: N Engl J Med 2009;360:2445-54.
Cox multivariate regression analysis of factors
that predict lung cancer
Parameter
Age
DLCO<80%
predicted
BMI
GOLD stage
I
II
III
IV
Hazard Ratio
95% CI
p value
1.02
1.00-1.04
0.029
1.76
1.15-2.69
0.009
0.95
0.92-0.99
0.011
3.05
2.06
1.67
Reference
1.41-6.59
1.01-4.18
0.81-3.44
0.005
0.044
0.159
Variables included in the model: age, BMI, pack-year history, smoking status,
GOLD, DLCO<80% and IC/TLC<0.25.