Centre for Human Drug Research, The Netherlands
Marlous Dillingh has a background in biomedical sciences. She is currently in training as a clinical pharmacologist at the Centre for Human Drug Research, Leiden, The Netherlands. Her main expertise is the integration of inflammation/immunology and pharmacology, applied in early phase clinical drug development, which is the focus of her PhD education.
Human in vivo models of systemic inflammation are used to study the physiological mechanisms of inflammation and the effect of drugs and nutrition on the immune response. Although in vivo lipopolysaccharide (LPS) challenges have been applied as methodological tool in clinical pharmacology studies, detailed information is desired on dose-response relationships, especially regarding LPS hyporesponsiveness observed after low-dose in vivo LPS administration. A randomized, double-blind, placebo-controlled study was performed with single ascending low doses of LPS (0.5-2 ng/kg body weight) to assess the in vivo inflammatory effects of low intravenous LPS doses, and to explore the duration of the induced LPS hyporesponsiveness assessed by subsequent ex vivo LPS challenges in healthy volunteers. The in vivo inflammatory response showed a dose-dependent increase in body temperature, heart rate, CRP and circulating cytokines (TNF-α, IL-1β, IL-6, IL-8) which showed clearly distinctive increases from placebo already at the lowest LPS dose level tested (p≤0.0001). Ex vivo LPS challenges were performed to estimate the duration and magnitude of LPS hyporesponsiveness by assessment of cytokine release. In vivo LPS administration dose-dependently induced a period of hyporesponsiveness in the ex vivo LPS-induced cytokine release, with maximal hyporesponsiveness observed at 6 hours, lasting no longer than 12 hours. For IL-6 and IL-8, indications for immune cell priming were observed. This study expands the knowledge about the dose-effect relationship of LPS-induced hyporesponsiveness. As such, the low-dose LPS challenge has been demonstrated to be a feasible methodological tool for future clinical studies exploring robust pharmacological or subtle nutritional immune-modulating effects.
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