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Study of the Effect of Innate on the Inflammatory Response to Endotoxin

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ClinicalTrials.gov Identifier: NCT01143480
Recruitment Status : Enrolling by invitation
First Posted : June 14, 2010
Last Update Posted : December 16, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )

Study Description
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Brief Summary:

Background:

- Innate immunity is the process by which white blood cells and other parts of the immune system sense and respond to potential infections by causing an inflammation. Researchers are interested in studying how the body responds to certain environmental factors, and whether the body s response can contribute to chronic illnesses or diseases such as asthma and certain types of cancers.

Objectives:

- To examine how specific genes and proteins in blood cells respond to environmental exposures.

Eligibility:

- Healthy volunteers between 18 and 45 years of age.

Design:

  • The study will involve one visit of 45 to 60 minutes.
  • Participants will be screened with a brief physical examination and finger stick to determine if they are eligible to donate blood for the study, and will complete a questionnaire about any medications or other drugs (e.g., cigarettes) they may be taking.
  • Participants will provide a blood sample for research purposes.

Condition or disease
Asthma Atherosclerosis Metabolic Syndrome Insulin Resistance Cancer

Detailed Description:

This research study will examine the role of innate immunity on the Inflammatory response of monocytes and macrophages to endotoxin. Approximately 1450 healthy participants aged 18 years and older will be identified and recruited from the Environmental Polymorphism Registry (EPR). The EPR is a long-term project to collect and store up to 15,000 DNA samples for use in research studies from individuals in the greater North Carolina Triangle Region. It is anticipated that approximately 50% of the participants contacted will enroll and about 15% of participants enrolled will withdraw.

This controlled, observational gene association study will recruit participants on the basis of genotype and then observe the phenotype of each participant. There are several SNPs of interest in the genes TIRAP, MyD88, ABCA1, CD14, CD44, ITIH3, ITIH4, TLR4, TNFa, TLR5. IRGM and APOL1. In addition there are alleles of interest in the gene ApoE. These alleles taken together are considered a polymorphism. For each polymorphism of interest a separate group of participants will be recruited (including heterozygous and homozygous for both the minor and major alleles for each SNP). A maximum of 200 mLs of blood will be obtained from each participant during one visit lasting approximately 1.5 hours. Blood monocytes will be isolated from the donated blood samples and cultured to obtain macrophages. The macrophages will be exposed ex vivo to an endotoxin (LPS) and to PAM3CSK4 to determine cell response depending on genotype. In studies of APOL1, a urine specimen will also be collected to evaluate for protein filtration.

The primary objective is to determine associations between select polymorphisms in genes [TIRAP (TIR Associated Protein), MyD88 (Myeloid Differentiation Primary Response Protein 88), ApoE (Apolipoprotein E), ABCA1 (ATP Binding Cassette Transporter A1), CD14, CD44, ITIH3, ITIH4, TLR4, TNFa, TLR5, IRGM and APOL1] and quantitative in vitro inflammatory functions of two cell types, the macrophage and neutrophil. The primary endpoints of this study for both cell types will be levels of 6 cytokines TNF alpha, IL-6, MIP-2, IL-8, MCP-1, and IFN-beta (ELISA) induced by LPS and by PAM3CSK4 plus baseline cytokine levels (no exposure to LPS or PAM3CSK4). Urinary levels of protein will be quantified in some studies as a measure of early kidney

dysfunction.

We hope the results of this study may lead to discovery of important information regarding the role of MDC1 (Mediator of DNA damage Checkpoint protein 1) in human disease, potentially identifying new targets for future studies.

Study Design
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Study Type : Observational
Actual Enrollment : 196 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Study of the Effect of Innate Immunity on the Inflammatory Response to Endotoxin
Actual Study Start Date : July 30, 2012
Groups and Cohorts
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Group/Cohort
ABCA1
SNP or allele of interest
APOE
SNP or allele of interest
APOL1
SNP or allele of interest
CD14
SNP or allele of interest
CD44
SNP or allele of interest
IRGM
SNP or allele of interest
ITIH3
SNP or allele of interest
ITIH4
SNP or allele of interest
MyD88
SNP or allele of interest
TIRAP
SNP or allele of interest
TLR4
SNP or allele of interest
TLR5
SNP or allele of interest
TNFa
SNP or allele of interest


Outcome Measures
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Primary Outcome Measures :
  1. The primary endpoints of this study are for both cell types and will be levels of 6 cytokines [TNF alpha, IL-6, MIP-2, IL-8, MCP-1, and IFN-beta (ELISA)] induced by LPS and by PAM3CSK4 plus baseline cytokine levels (no exposure to LPS or PAM3... [ Time Frame: After analysis ]
    The primary endpoints of this study are for both cell types and will be levels of 6 cytokines [TNF alpha, IL-6, MIP-2, IL-8, MCP-1, and IFN-beta (ELISA)] induced by LPS and by PAM3CSK4 plus baseline cytokine levels (no exposure to LPS or PAM3CSK4).


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Participants enrolled in Environmental Polymorphism Registry (EPR)@@@
Criteria
  • INCLUSION CRITERIA:
  • Male or female 18 years of age or older
  • Participants must be able to understand and provide written informed consent to participate in the study
  • Participants must be able to travel to the CRU
  • Willing and able to fast after midnight the night prior to their study appointment
  • Healthy participants as defined by the International Red Cross guidelines (Healthy means that an individual feels well and can perform normal activities. If the individual has a chronic condition such as diabetes or high blood pressure, healthy also means that they are being treated and the condition is under control).

EXCLUSION CRITERIA:

  • Use of nonsteriodal anti-inflammatory drugs (NSAIDs) within 5 days prior to enrollment visit (e.g., Motrin, ibuprofen, naproxen, and Advil)
  • Use of acetaminophen (Tylenol) within 5 days prior to enrollment visit
  • Use of cholesterol lowering drugs (statins) within 30 days prior to enrollment visit (e.g., Zocor, Mevacor, Lipitor, and Crestor)
  • Use of immunosuppressants or other immune-modifying drugs [e.g., Rituxan, Humira, Enbrel, Cyclosporin (Neoral, Sandimmune, and SangCya), and Azathioprine (Imuran)], Monoclonal antibodies [e.g., infliximab (Remicade)], and corticosteroids (e.g., prednisone, prednisolone and dexamethasone)
  • Current treatment for cancer with chemotherapy or radiation
  • Confirmed or suspected immunosuppressive or immunodeficient condition
  • GI or respiratory Illness within 5 days prior to enrollment visit, including cold or allergies
  • Smoked tobacco, chewed tobacco or used electronic cigarettes within 2 weeks prior to enrollment visit (for participants who provide a urine specimen, this will be defined by urine cotinine >200 ng/mL at visit)
  • Alcohol consumption greater than 2 standard drinks (1 standard drink contains 15 g of ethanol) per day within the last 24 hours prior to the enrollment visit
  • Body weight < 50 kg (<110 lbs)
  • Temperature > 37.6 C; blood pressure < 90/50 mm Hg or > 170/95 mm Hg; pulse rate < 50 or >100 beats/minute
  • Pregnant or suspected pregnancy
  • Chronic Kidney Disease

The PI may review medication use on a case by case basis and make a medical determination on the participant s eligibility. In these cases, the PI determination will be documented in the participant s chart.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01143480


Locations
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United States, North Carolina
NIEHS Clinical Research Unit (CRU)
Research Triangle Park, North Carolina, United States
Sponsors and Collaborators
National Institute of Environmental Health Sciences (NIEHS)
Investigators
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Principal Investigator: Michael B Fessler, M.D. National Institute of Environmental Health Sciences (NIEHS)
More Information
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Additional Information:

Publications:

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Responsible Party: National Institute of Environmental Health Sciences (NIEHS)
ClinicalTrials.gov Identifier: NCT01143480    
Other Study ID Numbers: 100129
10-E-0129
First Posted: June 14, 2010    Key Record Dates
Last Update Posted: December 16, 2020
Last Verified: November 30, 2020
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) ):
Endotoxin
Innate Immunity
Healthy Volunteer
HV
Additional relevant MeSH terms:
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Atherosclerosis
Metabolic Syndrome
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
 Metabolic Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases