Observing inflammatory processes in the body

Imaging of labeled monocytes after a heart attack (arrow). Left (complete heart with incision) and centre (section of the heart): fluorescence-labeled monocytes. Right: radioactively labeled monocytes (section of the heart).
© EIMI/M. Schäfers

Project title: Combining myeloid precursor immortalization, genome editing and genetic reporter systems for imaging of monocyte trafficking in inflammation and ischemia
Principal investigators: Johannes Roth, Michael Schäfers
Project time: 11/2017 - 12/2018
Project code: FF-2017-17

Monocytes are a group of immune cells which play a pivotal role in inflammation. The type of monocytes, as well as their number and their stage of development, determine whether an inflammation subsides or becomes chronic. The distribution of such monocytes in the body can be made visible by using optical imaging methods or those involving positron emission tomography (PET). These methods were already developed in previous CiM projects. So far, however, imaging for tracking monocytes has significant limitations. What is missing are suitable markers which allow repeated imaging of monocytes over the course of inflammatory reactions. Such markers are for example radiopharmaceuticals, which are injected for a study in tiny quantities in patients or model organisms such as a mouse, and which specifically bind and mark the cells being sought. Researchers at CiM now want to find out more about inflammatory processes and, using a new method, observe monocytes for the first time over the course of an inflammation in a living organism and in various organs. In this project Prof. Michael Schäfers, a nuclear physician, and Prof. Johannes Roth, an immunologist and paediatrician, are combining a variety of innovative genetic engineering and imaging methods in order to analyse the monocytes.

This approach involve producing monocytes from stem cells and modifying them with a so-called reporter gene. When these cells are injected, they are by themselves untraceable. The reporter gene, however, enables these monocytes to specifically enrich  radioactive substrates – allowing repeated measurements  in combination with a marker with a short half-life. These decompose so fast that no residues from the previous analysis can be seen anymore when the next analysis is carried out. This results in images of monocytes in the body that always show the latest stage of development in the inflammation. Researchers can therefore repeatedly visualize monocytes, and this then enables them to carry out whole series of investigations lasting hours, days or even weeks.

Because the researchers work with a radioactive substrate, they can use PET to make monocytes visible. The radioactivity permeates tissues more strongly than, for example, fluorescence markers do. This means that images can be reconstructed of the inside of the body much more sensitively, and the inflammatory cells can be quantified more precisely.

In this project the researchers want to gain a better understanding of how inflammations regulate themselves. Inflammations are always the first reaction to damaged or infected tissue. They can also, however, indicate autoimmune diseases or circulatory disorders. Most inflammatory reactions are regulated by the body itself without any problem. So far, however, it has not been clear how exactly that works. In treatments currently being used, inflammation is generally suppressed – which entails a high risk of side-effects. If the mechanisms of self-regulation were clear, they could also be used in treatments. It is for this reason that the imaging methods described above are combined with modern methods of genetic engineering. As a result, monocytes being used can be modified in their functions, and light can be shed on the molecular mechanisms involved in the regulation of inflammation. The methods being used in this research project are initially limited to research involving preclinical mouse models. Whether the findings lead to any applications for treating patients is something that only further research projects will be able to show.