Download Inhalation exposure to transition metals can facilitate sensitization to

Inhalation exposure to
transition metals can
facilitate sensitization to
an innocuous protein
antigen
Fraleigh NL, S Lefebvre, S Khurana, B Ross and
SA Ritz
1
Inhalation Tolerance
• Respiratory tract is
exposed to various
antigens
• Inhalation tolerance
results in the active
suppression of
responses towards
harmless antigens
• ~15% of the
industrialized world
has an allergy
Diaz-Sanchez Det al. 1996, Diaz-Sanchez D et al. 1997, Diaz-Sanchez Det al. 1999,
Rumold R et al. 2001, Swirski FK et al. 2002, Whitek MJ et al.. 2002, Steerenberg PA
et al. 2003, Steerenberg PA et al. 2004, Steerenberg PA et al. 2005, Riedl et al. 2005
Image from Wikipedia Commons
2
Health and Economic Effects
 In 2008, air pollution
is estimated to be
responsible for:
◦ ~21 000 premature
deaths
◦ ~11 000 hospital
admissions
◦ ~92 000 ER visits
◦ ~620 000 MD visits
◦ ~$8B in economic
costs
3
Particulate Matter
• Particulate matter is the solid portion
of air pollution
• Exacerbates cardiovascular and
respiratory disease in those at risk and
causes inflammation
• Dependent upon local environment
• Sudbury Particulate Matter contains
nickel
– Nickel induces inflammation and the
production of reactive oxygen species
Frampton MW et al. 1999, Ritz SA et al. 2002, Wallenborn JG et al. 2009, Riley MR et al. 2003
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Study Rationale
• Nickel may be able to act as an adjuvant
and induce allergic sensitization
• Mice will be exposed to a harmless
antigen (OVA) with or without Ni3S2, and
inflammatory and immune responses
assessed
– Hallmarks of allergic responses:
eosinophilia, IgE, Th2 cytokines
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Methodology
X
daily instillation of metals (i.n.)
(or saline control)
0 1
10
48h
daily OVA aerosolization
(or saline control)
Image from Charles River criver.com
6
Airway Inflammation
250 ng Ni3S2
OVA/saline
Ni (250 ng)/OVA
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Total Number of WBC in BAL of Acutely Treated Balb/c Mice
1.4e+6
1.2e+6
8.0e+5
6.0e+5
4.0e+5
2.0e+5
Treatment Groups
Ni(10
00)/O
VA
Ni(25
0)/O
VA
Ni(50
)/OV
A
OVA
/salin
e
0.0
Naiv
e Co
ntrol
White Blood Cells (cells/mL)
1.0e+6
8
Total Number of Eosinophils in Acutely Treated Balb/c Mice
20000
Number of Eosinophils (cells/mL)
15000
10000
5000
0
Naive Control OVA/saline Ni(50 ng)/OVA Ni(250)/OVA Ni(1000)/OVA
Treatment Groups
9
Methodology
X
daily instillation of metals (i.n.)
(or saline
control)
0 1
10
5 weeks
72h
daily OVA aerosolization
(or saline control)
challenge
with
aerosolized
OVA
10
Total Number of Cells in BAL of Rechallenged Balb/c Mice
1.4e+6
1.0e+6
8.0e+5
6.0e+5
4.0e+5
2.0e+5
Treatment Groups
Ni ( 1
000)
/O
VA R
VA R
50)/O
Ni ( 2
0)/O
VA R
Ni ( 5
OVA
/salin
eR
0.0
Naiv
e c on
trol R
Total Number of Cells (cells/mL)
1.2e+6
11
Number of Eosinophils in BAL of Rechallenged Balb/c Mice
12000
8000
6000
4000
2000
Treatment Groups
Ni/O
VA
1000
ng
Ni/O
VA
250
ng
Ni/O
VA
50 n
g
OVA
/salin
e
0
Naiv
e Co
ntrol
Eosinophils (cells/mL)
10000
12
• Histological processing of lungs
• OVA-specific Immunoglobin ELISA
• Repeat the experiment with a dose
reflecting the results obtained from the
pilot study
13
Take Home Message
• Nickel is able to induce an inflammatory
response leading to increased levels of
inflammation
• Groups that were treated with low doses
of Ni and rechallenged with OVA had
increased levels of eosinophilia
• Low doses of Ni may act as an adjuvant
and elicit allergic sensitization to another
antigen
14
Acknowledgements
• I would like to thank the
members of Team Ritz for
all of their help and
support
–
–
–
–
Dr. Stacey Ritz
Sandhya Khurana
Sebastien Lefebvre
Sarah White
• Manel Jordana Lab at
McMaster University
• Joe Eibl and NOSM lab
• CIHR Team in Gender
Environment and
Health
• NOSM/NOSM FA
Research