The search for human complement challenge models

‘During my pharmacy studies I did an internship at CHDR, working with Matthijs Moerland’s group,’ Van den Noort explains. ‘At the time, the team was working on an assay to predict infusion reactions. These are rare reactions that may occur after the injection of a drug, due to complement activation — for example, a drop in blood pressure, or a skin rash. Back then, we were looking for an in vitro test: if you add the drug to blood from the participant in a test tube, can you predict who will get an infusion reaction?’

Partly due to the rarity of infusion reactions, this search did not yield definitive answers. After gaining her master’s degree, Van den Noort returned to CHDR to begin her PhD research on complement. Meanwhile, the scope of the question had broadened. It was no longer just about predicting infusion reactions, but also about developing an in vivo challenge model to measure complement activation.

[text continues below the photo]

Innate immunity

The complement system is part of the innate immune system. It consists of dozens of proteins, which can successively activate each other in three different cascades. The end products of these pathways are capable of killing bacteria and disabling viruses, attracting phagocytes, or triggering inflammatory responses. Recent research shows that complement activation may play a role in unwanted immune responses, such as autoimmune diseases and neurodegeneration. There are also compounds being developed to activate complement in the context of cancer immunotherapy. Van den Noort: ‘Complement is hot right now. For almost every component of the complement system, there’s currently a compound in development.’

In recent years, CHDR has developed many challenge tests to map activation of the innate immune system. Various LPS challenges have been developed in-house that activate the innate immune system via the TLR4 receptor, whether in blood (in vitro or ex vivo), in vivo in the skin, or systemically. Another model uses imiquimod, which triggers an innate immune response via the TLR7 receptor. In combination with skin biopsies and suction blisters, these challenge models offer detailed insight into the innate immune response. Van den Noort: ‘Equipped with these validated challenge models, we are looking to contribute to the in vivo measurement of complement activation.’

Detecting complement activation

Demonstrating complement activation is no easy task, and the team’s attempts to detect activated complement in the blood or in skin biopsies have not yet been unequivocally successful. Van den Noort: ‘Evolutionarily, the complement system is the oldest part of our immune system, but it’s also the part we know the least about. For instance, we don’t yet know how long the different components of the cascade are detectable for. On the other hand, we do know that some components only exist for a short time. That makes it difficult to design assays: if you don’t detect any activation, is there really no activation, or did you just biopsy a minute too late to find the activated protein?’

Van den Noort does not know whether she will succeed in finding an in vivo model that will allow her to detect complement activation in the skin or blood of study participants. But she is optimistic, thanks to CHDR’s previous successes in measuring innate immunity. ‘I know it’s a search for a needle in a haystack. But luckily, it’s a haystack that we already know pretty well!’