Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia

Overview

Iron affects immunity. However, the exact effect of iron on the innate immune response is not known. Animal data suggest that iron administration induced oxidative stress which enhances the innate immune response, whereas iron chelation has the opposite effect. The investigators tested the hypothesis that administration of iron sucrose 1.25 mg/kg augments the innate immune response, and iron chelation by deferasirox 30 mg/kg attenuates the innate immune response during human experimental endotoxemia.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Basic Science
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 2010

Detailed Description

Systemic inflammation is accompanied by profound changes in iron distribution, mainly under the influence of hepcidin, leading to sequestration of iron in macrophages of the reticuloendothelial system, and ultimately anemia of inflammation. This redistribution of iron may represent an effective defense mechanism against a variety of pathogens, that need iron for replication and growth. The fact that iron withholding strategy is such a highly conserved part of the innate immune response illustrates that iron homeostasis and immunity are closely related. Concordantly, several studies in animal models have revealed immune modulatory effects of both iron and iron chelation: Iron sucrose has been shown to potentiate the inflammatory response and associated mortality, while iron chelation appears to attenuate inflammation and improve outcome in murine models of inflammation and sepsis. The immune modulatory effects of iron supplements and chelators are mainly attributed to their ability to potentiate or reduce the formation of reactive oxygen species (ROS). A subfraction of non-transferrin bound catalytically active iron, labile plasma iron, is thought to be responsible as this free iron is able to easily donate or accept electrons, thereby fueling redox reactions. Oxidative stress is associated with propagation of the immune response, endothelial dysfunction, and contributes to the organ damage that occurs during systemic inflammation. In accordance, anti-oxidants exert anti-inflammatory effects. As such, iron chelation has been suggested to be a valuable adjuvant therapy during infection for two distinct reasons: inhibition of bacterial growth and protection of organs against inflammation induced oxidative stress. Effects of iron status on the immune response has up till now mainly been investigated in in vitro and in animal models, often using supra-therapeutic dosages of iron donors or iron chelators. Data on the effect of iron loading and iron chelation during systemic inflammation in humans are lacking. The objectives of the present study were to investigate the acute effect of therapeutic dosages of iron loading and iron chelation therapy on iron homeostasis, oxidative stress, the innate immune response, and subclinical organ injury during systemic inflammation induced by experimental endotoxemia in humans in vivo.

Interventions

  • Drug: iron sucrose
    • 1.25 mg/kg iron sucrose is administered intravenously 1 hr before endotoxin administration
  • Drug: Deferasirox
    • 30 mg/kg deferasirox is administered orally 2 hrs before endotoxin administration.
  • Drug: endotoxin
    • at t=0 2ng/kg purified E.Coli endotoxin is administered intravenously
  • Drug: Placebo
    • At t=-2 hrs starch is dissolved in water to serve as a placebo for exjade. It is prepared and administered orally by a research nurse that is unblinded to the protocol. At t=-1 hrs 0.9% NaCl is administered intravenously serving as a placebo for iron sucrose. The infused volume is identical, and the syringes en tubes are blinded by aluminum foil. The administration is carried out by a research nurse that is unblinded to the protocol.

Arms, Groups and Cohorts

  • Active Comparator: Iron loading
    • Subjects will receive 1.25 mg/kg iron sucrose intravenously 1 hour before endoxin administration 2ng/kg.
  • Active Comparator: Iron chelation
    • Subjects will receive 30mg/kg deferasirox orally 2 hours before endotoxin administration 2ng/kg.
  • Placebo Comparator: Placebo
    • Subjects will receive placebo instead of iron chelation or iron loading before endotoxin administration

Clinical Trial Outcome Measures

Primary Measures

  • TNF-alfa
    • Time Frame: Level of TNF-alfa 90 minutes after endotoxin administration
    • Level of TNF-alfa 90 minutes after endotoxin administration

Secondary Measures

  • Cytokines
    • Time Frame: 24 hrs after the administration of endotoxin
    • Levels of TNF-alfa, IL-6, IL-10 IL-1RA, ICAM and VCAM.
  • Oxidative stress
    • Time Frame: 24 hrs after the administration of iron / iron chelator / placebo
    • Several parameters of oxidative stress are measured: TBARS,carbonyls,oxidative radical production of neutrophils, ferric reducing ability of plasma.
  • Hemodynamic response
    • Time Frame: 24 hours after the administration of endotoxin
    • Hemodynamic sequelae of endotoxin administration are monitored (heart rate, blood pressure) and the response of fore arm vessels to the infusion of vasoactive medication (norepinephrine, acetycholine, and nitroglycerine) is measured.

Participating in This Clinical Trial

Inclusion Criteria

  • male – healthy – between 18 and 35 years of age Exclusion Criteria:

  • smoking – use of prescription drugs – febrile illness < 2 weeks before the study date – abnormalities found at screening – participation in another trial in the preceding 6 months – iron disorders in the family

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 35 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Radboud University Medical Center
  • Collaborator
    • ZonMw: The Netherlands Organisation for Health Research and Development
  • Provider of Information About this Clinical Study
    • Principal Investigator: Peter Pickkers, MD. PhD – Radboud University Medical Center
  • Overall Official(s)
    • Peter Pickkers, MD, PhD, Principal Investigator, Radboud University Medical Center

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