Clinical trial NCT01349699: Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia
Official title: Effects of Iron Loading and Iron Chelation Therapy on Innate Immunity During Human Endotoxemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Systemic Inflammatory Process
Anemia
Keywords: endotoxemia
inflammation
iron
iron chelation
cytokines
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
First posted: 2011-05-06
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: TNF-alfa
timeFrame: Level of TNF-alfa 90 minutes after endotoxin administration
Secondary outcomes:
measure: Cytokines
timeFrame: 24 hrs after the administration of endotoxin
measure: Oxidative stress
timeFrame: 24 hrs after the administration of iron / iron chelator / placebo
measure: Hemodynamic response
timeFrame: 24 hours after the administration of endotoxin
Other outcomes:
Locations:
Study officials:
affiliation: Radboud University Medical Center
name: Peter Pickkers, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: