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

18 Years
Open (Enrolling)
Asthma, Atherosclerosis, Metabolic Syndrome, Insulin Resistance, Cancer

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Trial Information

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

This research study will examine the role of innate immunity on the Inflammatory response of
monocytes and macrophages to endotoxin. A total of 559 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.

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, and TNFa. 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 one hour. 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.

The primary objective is to determine associations between select polymorphisms in four
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, and TNFa] 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).

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.

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).


- 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)

- History of being treated for cancer by chemotherapy or radiation

- Confirmed or suspected immunosuppressive or immunodeficient condition

- GI or respiratory Illness within 5 days prior to enrollment visit, including cold or

- Smoked tobacco within 2 weeks prior to enrollment 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

Type of Study:


Study Design:


Principal Investigator

Michael B Fessler, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Institute of Environmental Health Sciences (NIEHS)


United States: Federal Government

Study ID:




Start Date:

May 2010

Completion Date:

Related Keywords:

  • Asthma
  • Atherosclerosis
  • Metabolic Syndrome
  • Insulin Resistance
  • Cancer
  • Endotoxin
  • Cytokines
  • Gene Association
  • Inflammatory Response
  • Healthy Volunteer
  • HV
  • Asthma
  • Atherosclerosis
  • Insulin Resistance
  • Metabolic Syndrome X



NIEHS Clinical Research Unit (CRU) Research Triangle Park, North Carolina