In Vivo Effects of C1-esterase Inhibitor on the Innate Immune Response During Human Endotoxemia

Rationale:

There is an unmet need for novel therapeutic agents focused on the complications caused by acute and excessive activation of the innate immune response after injury. As this activation responds poorly to currently used therapy including inhaled steroids novel agents need to be tested, developed or applied. C1INH comprises a potential important target drug for antagonism of the excessive activation of the innate immune response during acute inflammation seen after injury. This might be achieved by inhibiting the redistribution and homing of cells to inflammatory tissues.

Before going to a clinical trial in injured human subjects we want to perform a pilot study in healthy volunteers to exploit the "human endotoxemia model". The human endotoxemia model permits elucidation of key players in this pro-inflammatory response in humans in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting. The model bears striking resemblance to LPS models in animals. These latter studies have shown that C1INH protects from neutrophil mediated disease [1-4]. Together with the finding that C1INH has been shown to be safe in the treatment of humans, we propose to use this protein in the treatment of neutrophil driven acute inflammation such as seen after injury.

Objectives:

Primary objective: The primary objective of the study is to determine the effect of C1INH on systemic activation of the innate immune response induced by LPS challenge. This response will be objectivised by measurement of enhanced TNF-α levels 90 min after LPS challenge.