Immune System Responses Related to Environmental Uranium Exposure – DiNEH Project Results
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Immune System Responses Related to Environmental
Uranium Exposure – DiNEH Project Results
E. Erdei & J. LewisUniversity of New Mexico, Health Sciences Center,
College of Pharmacy, Community Environmental Health Program
Navajo Nation Human Research Review Board Conference
Window Rock, AZ
November 16, 2011
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Environmental Legacy Exposures Increase the Likelihood of Several Diseases: Autoimmune
DiseaseFigures below show similar increases in risks for autoimmune disease (self-reported) based on an increase from 1 to 2 activities
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DiNEH Survey Responses
35.9%
25.1%
17.1%
6.2% 5.4% 5.1%3.5% 3.1% 3.1% 2.5%
45.4%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Prevalence of Self-Reported Health Conditions Among 1,304 DiNEH Survey Participants
(*Cancer prevalence based on 1,011 participants surveyed)
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Goal of this portion of the study
• Direct response to community members’ requests for research on immune system function during the capacity building and environmental risk evaluation work
• Address possible pathways within the human body in association with environmental uranium and other heavy metal exposures
• Find early indicators of
health effects
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DiNEH biological sample collection
• DiNEH project participants from 20 chapters
• Samples collected from 267 individuals
• A subset has been analyzed for immune biomarkers (N=65)
• Early markers, showing alterations
in immune cell distribution and activity
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Flow cytometry measurements
• Lymphocyte subpopulations from whole blood samples.
• Becton Dickinson Simultest IMK Plus lymphocyte kit was used.
• 6 cell populations were measured:– T cells (CD3+), T helpers (CD4+), T suppressors
(CD8+); – B cells (CD19+); – HLA-DR+ cell activation in T cells and– B cells and other cell types; NK cells
(CD3-/CD16+/CD56+).
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UNM HSC Core Facility
• Director: Dr. Bruce Edwards
• Flow cytometry machine
• FACScan 2 lasers, 2-color
simultaneous detection of lymphocytes
• Membrane markers, CD coding
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Flow cytometry results I.CD3+ T cells (in %) among DiNEH participants
y = 25.601x + 44.298
R2 = 0.0446
0
10
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90
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
Exposure score
Perc
en
tag
e o
f cell
s
CD19+ B cells (in %) among DiNEH participants
y = 16.366x + 0.8651
R2 = 0.1538
0
5
10
15
20
25
30
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
Exposure Score
Per
cen
tag
e o
f ce
lls
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Flow cytometry results II.
• Increased percentage of activated T cells
• Decreased percentage of activated B cells
• Decoupling of T cell and B cell activities suggest altered immune response among this subset of participants
• Can lead to lower production of protective antibodies
• Preliminary interpretation of data; more complex modeling incorporating other variables pending
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Serum cytokines
• Cytokines are small molecular weight proteins produced by immune cells and other cells through the human body
• Their role is to promote communication, activation processes in the immune system
• Cytokine productions show immune status and disease developmental pathways
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Serum cytokine measurements
• Applied xMAP multiplexing technology
• UNM HSC Core Facility- Luminex 100™ detection (96-well format)
• Detection of 10 human serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, INF-γ, TNF-α, and
GM-CSF) high sensitivity assay
• Uses only 50 μl of serum sample/ participant
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Serum cytokine concentrations related to environmental uranium waste exposures
IFN-g cytokine and Exposure Score among DiNEH project participants
y = 0.0832x + 0.0385
R2 = 0.0265
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
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0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70
Exp. score
IFN
-g [
pg
/ml)
IL-4 (hypereactivity) cytokine production and Exposure Score among DiNEH participants
y = 0.2936x + 0.1276
R2 = 0.1202
0
0.1
0.2
0.3
0.4
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0.6
0.7
0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70
Exp. score
IL-4
cc.
[pg
/ml]
Interleukin-8 (IL-8; mucosal protection) cytokine and Exposure Score among DiNEH project participants
y = 3.8629x + 2.2598
R2 = 0.00660
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0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70
Exp. Score
cyto
kin
e cc
. [p
g/m
l]
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Serum cytokine concentrations (pg/ml) related to environmental uranium
waste exposures (N=47)• Percent of variance by exposure for IL-4 and IL-1ß suggests a
potential inflammatory process
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ConclusionsBased on our preliminary analysis• DiNEH participants with increased exposure to
uranium waste had increased number of activated T cells and decreased activity of B cells and other antigen-producing cells
• If consistent w/ other modeling results (e.g. water source) – indication of the decoupling of the immune response
• Alterations in cytokine production indicative of the presence of an inflammatory response
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Future directions
• These results are based on our preliminary analyses – work in progress
• To continue to complete immune assays for entire sample set
• Further modeling works will allow us more detailed evaluation of suggestive inflammatory response
• In connection with other pathway analyses –cardiovascular process
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DiNEH Acknowledgements
• NIEHS, EPA and UNM for financial support• Community Advisory Board
– Ed Carlisle, Jay DeGroat, Herbert Enrico, Thomas Manning,Sr., Lynnea Smith, Jean Whitehorse,
• UNM-HSC Community Environmental Health Program & Clinical and Translational Science Center
– Johnnye L. Lewis, PhD; Miranda Cajero, BCH; Matthew Campen, PhD; Jeremy DeGroat; Mallery Downs, RN; Eszter Erdei, PhD; Molly Harmon; Gabriel Huerta, PhD; Curtis Miller; Bernadette Pacheco; Glenn Stark; Mary Woodruff; research nursing support
• Crownpoint Service Unit, I H S– Virgil Davis
• Navajo Area IHS– Lisa Allee, CNM; John Hubbard; Ryan
Johnson, MD; Doug Peter, MD• UT-Houston Nephrology
– Donald Molony, MD• Southwest Research Information Center
– Chris Shuey, MPH, Sarah Henio-Adeky, Teddy Nez, Sandy Ramone
• Students– Jamie deLemos, PhD – Tufts Univ.– Christine George – Stanford Univ.– Tommy Rock, MA, UNM Health Policy
Student– Christine Samuel-Nakamura, PhD
Candidate, UCLA• Dartmouth
– Ben Bostick, PhD• University of Arizona Cancer Center &
Northern Arizona University, NACRP– Jani Ingram, PhD, Margaret Briehl, PhD
• USEPA Region IX– Harry Allen, Rich Bauer, Clancy Tenley
• State of New Mexico Diagnostic Laboratory• Navajo Nation EPA Air Quality Division, Public
Water Supply Supervision Program, Superfund Program
• Navajo Nation Division of Health• Former Contributors:
– Bess Seschillie, Bernice Norton, Jerry Elwood, Harrison Gorman, Harris Arthur (in memoriam), Alta McCabe, Margaret Menache, PhD, Alexis Kaminsky, PhD; Eastern Navajo Health Board
• Thanks to the many others who’ve contributed
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Project funding support
• DiNEH project – supported through the following grants
• NIEHS, RO1 ES014565; R25 ES013208; P30 ES-012072;
• USEPA/ERRG pass through contract; with support from DHHS/NIH/NCRR #1UL1RR031977-01
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Questions?
THANK YOU!