NUCDF. Why is the immune system important? The immune system is composed of organs and cells. July 20, 2013
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1 NF Virtual Conference Presentation Metabolism, Infection and Immunity in Urea Cycle Disorders Peter J. Mc Guire MS, MD Physician-Scientist NATIONAL HUMAN GENOME RESEARCH INSTITUTE U.S. Department of Health and Human Services National Institutes of Health Why is the immune system important? The immune system is composed of organs and cells Organs NF Cells Foundation 1
2 NF Virtual Conference Presentation The immune system has many different type of cells Bone graft Macrophage Mast cell Eosinophil Erythrocytes Marrow Basophil Monocyte Bone Megakaryocyte Hematopoietic stem cell Multipotential stem cell Myeloid progenitor Neutrophil cell Platelets Lymphoid progenitor cell Dendritic cell T lymphocyte B lymphocyte C D F Natural killer cell Why is the immune system important? Body learns to defend itself by: Natural infection N U Vaccination How does vaccination work? Key: infec on T cells and B cells Protec ve an bodies vaccina on Weeks Immune memory ears Days ears Foundation 2
3 NF Virtual Conference Presentation Why study immune function in or any metabolic disorder? Because: Infection is bad for patients with Our question: Does having a affect immune function? Infection is bad for patients with Point #1: Infection increases caloric requirements 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 Point #2: Infection can cause increased muscle breakdown and elevated ammonia Muscle Liver Amino acids NF Blood Ammonia Foundation 3
4 ) ) NF Virtual Conference Presentation Infection is bad for patients with Point #3: Infection can inhibit urea cycle metabolism Inhalation based infection CPS1 enzyme A 150 n CP nmol/mg/min n/h Cit nmol/g protein OTC enzyme 100 Control Infected Enzyme activity decreases Urea cycle amino acids decrease McGuire et al., 2013 (in review) Infection is bad for patients with Point #4: The immune response may be part of the problem. cytokines Immune cells text each other by cytokines May be innocent bystanders (e.g. liver) 1.5 Ammonia metabo olism (control ratio) CPS1 liver cells IL-1β IL-6 WT spf-ash WT spf-ash NF PBS TNFα IL-1β IL-2 IL-6 IFNα IFNβ IFNγ ng/ml 0.1 ng/ml 1 ng/ml 10 ng/ml Cytokines produced as part of the immune response inhibit ammonia metabolism in human liver cells. A Infection is bad for patients with Point #5: What do we see clinically with infection? s Hospital days * Other Diet Infection B s IV scavengers (% HA events Other Diet Infection CPS1/b-actin (control ratio) Summary: * hospital admissions hospital days Ammonul use TNFα McGuire et al., 2013 (J Peds, accepted ) Foundation 4
5 NF Virtual Conference Presentation Immune function in Since infection can be very serious... How well does the immune system function in patients t with? Can patients with be protected from illnesses by vaccination? Immune function and 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 enzyme deficiencies are also present in immune organs and cells Immune function and What don t we know? A lot How well do immune cells from patients with function? NF Do patients with develop immune protection following vaccination? Foundation 5
6 NF Virtual Conference Presentation Vaccination in 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) data)nf Flu season Infection 5 Diet 0 Peter Mc Guire (unpublished Seasonality of elevated blood ammonia ents HA eve August September October November December January February March April May June July Foundation 6
7 NF Virtual Conference Presentation Metabolism, INfection and Immunity in Inborn Errors of Metabolism Peter J. Mc Guire MS, MD Physician-Scientist NATIONAL HUMAN GENOME RESEARCH INSTITUTE U.S. Department of Health and Human Services National Institutes of Health MINI MINI Study Participants Study Who can participate? We can not enroll anyone who: To be in the study a person must: Is under 2 years of age Be at least 2 years of age Is being treated for an intercurrent infection with Have a biochemically antibiotics, has evidence of an confirmed diagnosis of a acute infection, or has 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 NF Foundation 7
8 NF Virtual Conference Presentation How can I participate? At the NIH Clinical Center Out-patient In-patient +/- outpatient Samples only America s Research Hospital Travel and lodging arranged and covered by NIH Meals covered by NIH Family members welcome Children s Inn at NIH NF Foundation 8
9 NF Virtual Conference Presentation 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 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. NF How can I participate? antibodies to childhood vaccinations, inflammation markers, offer vaccination for flu and hepatitis A Dietary analysis; nitrogen metabolism; fatty acid, vitamin and micronutrient status; body composition; bone density; energy How can I participate? samples Participating as an in-patient +/- out-patient Immune profiling Immune cell populations and function, total antibodies, offer vaccination for flu and hepatitis A Nutritional profiling expenditure; nitrogen balance Address patient needs Dentistry, Neurology, Physical Medicine and Rehabilitation, Endocrinology, etc. 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 Foundation 9
10 NF Virtual Conference Presentation Using humanized mice to study immune cell function NSG Mouse Human Cord Blood Cells Humanized Mouse Can transplant: Hematopoietic stem cells from cord blood Peripheral white blood cells from blood samples Uses: Safely study infection Immune cell function Vaccination Immune organ function MINI Study contact information Principal Investigator Peter J. Mc Guire MS, MD Study Coordinator Janet Shiffer, NP Telephone Website Foundation 10
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