Page 1
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 1
Metabolism, Infection and Immunityin Urea Cycle Disorders
Peter J. Mc Guire MS, MDPhysician-Scientist
National Institutes of Health
U.S. Department of Health and Human Services
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Why is the immune system important?
The immune system is composed of organs and
cellsOrgans CellsNUCDF
Page 2
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 2
The immune system has many different type of cells Bone graft
Hematopoieticstem cell
Macrophage
ErythrocytesEosinophil
Megakaryocyte
Mast cell
Basophil
Monocyte
Marrow
Bone
Multipotentialstem cell
Platelets
Neutrophil
T lymphocyte
Natural killer cell
Dendritic cell
B lymphocyte
Lymphoid progenitor cell
Myeloid progenitor
cell
Why is the immune system important?
• Body learns to defend itself by:
– Natural infection
– Vaccination
infec on
Y Y Y Y Y Y
Y Y Y
Y YY
YY
Y
T‐cells and B‐cells
Protec ve an bodies
Key:
How does vaccination work?
vaccina on
Y Y Y Y Y Y
Y Y Y
Y Y Y Y Y
Y Y Y Y Y
Y Y Y Y Y Y Y Y
Y Y Y
Y Y Y Y Y Y
Y Y Y Y Y Y Y Y Y
Y Y Y “Immune memory”
Weeks Years Days Years
Y Y Y
NUCDF
Page 3
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 3
Why study immune function in UCD or any metabolic disorder?
• Because:– Infection is bad for patients
with UCDwith UCD
• Our question:– Does having a UCD affect
immune function?
Infection is bad for patients with UCD
• Point #1: Infection increases caloric requirements
F 1° C f f– For every 1° C of fever, metabolic rate can increase 10% or more
– Problem: need more calories, but you don’t feel like eating
Infection is bad for patients with UCD
• Point #2: Infection can cause increased muscle breakdown and elevated ammonia
Muscle UCD Liver
Amino acids
Blood
Ammonia
NUCDF
Page 4
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 4
Infection is bad for patients with UCD
• Point #3: Infection can inhibit urea cycle metabolism
A150
n100
n/h Control
CPS1 enzyme OTC enzyme
WT
spf-a
sh0
50
100
CP
nm
ol/m
g/m
in
WT
spf-a
sh0
10
80
90
Cit
nm
ol/g
pro
tein Infected
McGuire et al., 2013 (in review)
Inhalation based infectionEnzyme activity decreasesUrea cycle amino acids decrease
Infection is bad for patients with UCD
• Point #4: The immune response may be part of the problem.
1.0
olis
m
) IL 6
IL-1β
CPS1 liver cells
1.5
0 ng/m
L
0.1 ng
/mL
1 ng/m
L
10 ng
/mL
0.0
0.5
Am
mo
nia
me
tab
o(c
on
tro
l ra
tio
) IL-6
TNFα
Cytokines produced as part of the immune response inhibitammonia metabolism in human liver cells.
Immune cells “text”each other by cytokines
May be innocent bystanders (e.g. liver)
cytokinesPBS
TNFαIL
-1βIL
-2IL
-6IF
NαIF
NβIF
Nγ0.0
0.5
1.0
CP
S1
/b-a
ctin
(co
ntr
ol r
atio
)
Infection is bad for patients with UCD
• Point #5: What do we see clinically with infection?
67
s
*100
s ) *
A B
Summary:
McGuire et al., 2013 (J Peds, accepted )
Other
Diet
Infe
ctio
n0123456
Ho
spit
al d
ays
Other
Diet
Infe
ctio
n0
20
40
60
80
IV s
cave
ng
ers
(% H
A e
ven
ts * hospital admissions
hospital daysAmmonul use
NUCDF
Page 5
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 5
Immune function in UCD• Since infection can be very
serious...
– How well does the immune t f ti i ti t ithsystem function in patients with
UCD?
– Can patients with UCD be protected from illnesses by vaccination?
Immune function and UCD
• What do we know? Not much, but…– Immune cells don’t like high levels
of blood ammonia
– Immune cells don’t like nutritional deficiencies
– Certain UCD enzyme deficiencies are also present in immune organs and cells
Immune function and UCD
• What don’t we know? A lot…
– How well do immune cells from patients with UCD function?with UCD function?
– Do patients with UCD develop immune protection following vaccination?
NUCDF
Page 6
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 6
Vaccination in UCD• Regular childhood vaccinations are
recommended including influenza (Barshop and Summar, 2008)
• Childhood vaccines are not associated with adverse events (Klein et al, 2011 and Morgan et al, 2011)
• Do patients with IEM respond? (Brady, 2005)
Flu season
Seasonality of elevated blood ammonia
ents
15
20
HA
eve
August
Septe
mber
October
Novem
ber
Decem
ber
Januar
y
Febru
ary
Mar
chApril
May
June
July
0
5
10
Infection
Diet
Peter Mc Guire (unpublished data)
NUCDF
Page 7
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 7
www.nationaljewish.org
Metabolism, INfection and Immunity in Inborn Errors of Metabolism
Peter J. Mc Guire MS, MDPhysician-Scientist
National Institutes of Health
MINIU.S. Department of Health and Human Services
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Study
MINI Study Participants
Who can participate?To be in the study a person must:
• Be at least 2 years of age
• Have a biochemically confirmed diagnosis of a UCD
We can not enroll anyone who:• Is under 2 years of age
• Is being treated for an intercurrent infection with antibiotics, has evidence of an acute infection, or has confirmed diagnosis of a UCD
or related disorder
,hyperammonemia
• Has received another vaccine or immune modulating drug within the past 6 months
• Is currently living in a hospital
• Does not have a local / regular physician to manage their UCD
NUCDF
Page 8
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 8
How can I participate?
• At the NIH Clinical Center– Out-patient
– In-patient +/- outpatient
• Samples only
America’s Research HospitalTravel and lodging arranged and covered by NIH
Meals covered by NIHFamily members welcome
Children’s Inn at NIHNUCDF
Page 9
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 9
How can I participate?
• Participating as an out-patient– Immune profiling
• Immune cell populations and function, total antibodies, antibodies to childhood vaccinations, inflammation markers, offer vaccination for flu and hepatitis Aoffer vaccination for flu and hepatitis A
– Nutritional profiling• Dietary analysis; nitrogen metabolism; fatty acid, vitamin and
micronutrient status; body composition; bone density
– Address patient needs• Dentistry, Neurology, Physical Medicine and Rehabilitation,
Endocrinology, Immunology, etc.
How can I participate?
• Participating as an in-patient +/- out-patient– Immune profiling
• Immune cell populations and function, total antibodies, antibodies to childhood vaccinations, inflammation markers, offer vaccination for flu and hepatitis Aoffer vaccination for flu and hepatitis A
– Nutritional profiling• Dietary analysis; nitrogen metabolism; fatty acid, vitamin and
micronutrient status; body composition; bone density; energy expenditure; nitrogen balance
– Address patient needs• Dentistry, Neurology, Physical Medicine and Rehabilitation,
Endocrinology, etc.
How can I participate?
• Participating as samples only– Blood- during infectious illnesses (e.g. Flu) and well
states
– Cord blood – humanized mouse models
– Tissues that result from a medical procedure including, but not limited to, liver, tonsil, spleen samples
NUCDF
Page 10
NUCDF Virtual Conference Presentation Metabolism, Infection and Immunity in UCD
July 20, 2013
©2013 National Urea Cycle Disorders Foundation www.CureUCD.org 10
Using humanized mice to study immune cell function
• Uses:– Safely study infection
NSG Mouse
Human
Humanized Mouse
– Immune cell function
– Vaccination
– Immune organ function
Cord Blood Cells
Can transplant:Hematopoietic stem cells from cord bloodPeripheral white blood cells from blood samples
www.genome.gov/mini
MINI Study contact informationPrincipal Investigator
Peter J. Mc Guire MS, MD
Study CoordinatorJanet Shiffer, NP
Telephone301-451-9145
Websitehttp://www.genome.gov/mini
[email protected]
NUCDF
