果冻传媒

Our immune system plays an important role in keeping our bodies healthy. For example, the immune system is involved in arteriosclerosis, cancer, and many other diseases. In her research, De Dreu therefore wanted to develop therapies that influence the immune system in order to direct it to remedy or reduce the disease symptoms itself. One way to influence the immune system is with cytokines. These are small proteins that are produced by and influence immune cells. Cytokines are already used in the treatment of various diseases, such as different types of cancer, but this is often accompanied by unpleasant side effects. This is because our body clears these cytokines very quickly. To compensate for this, very high doses are required. In addition, cytokines can affect different cells throughout our body, which can also intensify these side effects. With her research, De Dreu therefore wanted to use nanoparticles to deliver these cytokines locally to the immune cells, so that they have less effect on cells that are not the target of the treatment and can therefore be administered in lower doses. With this research, De Dreu has taken the first steps in this direction.

Nanoparticles for immunotherapy

The nanoparticles used are inspired by nanoparticles found in the human body.  The human body contains various nanoparticles that transport molecules throughout the body. An example of this is high-density lipoprotein (HDL), also known as 'good cholesterol'. HDL can be described as a tiny lipid particle surrounded by a protein. This protein is apolipoprotein A1 (ApoA1). Thanks to this protein, these lipid particles remain stable in our body and do not fall apart. But ApoA1 also ensures that these lipid particles can interact with different cells in our body in order to transport different molecules, including to the cells of our innate immune system. By using ApoA1 to make nanoparticles, the nanoparticles remain stable and can interact with cells from the innate immune system. It also offers the possibility of incorporating other proteins into these nanoparticles by linking them to ApoA1.

In this study, De Dreu linked ApoA1 to various immune-regulating proteins such as cytokines or antigens. These proteins are called ApoA1-cytokine or ApoA1-antigen fusion proteins. It was demonstrated that these fusion proteins can integrate into stable nanoparticles, regardless of the size of the linked protein.

After injection (via a vein or into a muscle), these nanoparticles end up in organs that are rich in cells of the innate immune system. This was demonstrated in both mice and monkeys. The nanoparticles are mainly taken up by certain immune cells, such as macrophages and dendritic cells, but not by T cells or B cells.

Various applications of nanoparticles

De Dreu investigated two possible applications for these nanoparticles. The first is the treatment of a weakened immune system, for example after a serious infection such as sepsis. She created nanoparticles with ApoA1-IL-4 fusion proteins and demonstrated that these can reactivate the immune system in both mice and human cells in the lab.

De Dreu also developed nanoparticles that can serve as vaccines, for example against seasonal diseases such as influenza, or even against cancer. She showed that substances that activate the immune system (adjuvants) can easily be added to the nanoparticles. By using different combinations of adjuvants, the nanoparticles triggered a strong immune response in mice, with both antibodies and T cells. In a mouse model for cancer, they even prevented tumors from developing.

With these results, De Dreu demonstrates that this platform with fusion proteins and nanoparticles is versatile and has potential for use in various medical applications.

Title of PhD thesis: 鈥淓ngineering fusion proteins for nanomedicine-based immunotherapy鈥�

Supervisors: Willem Mulder, Maarten Merkx and Roy van der Meel