Neutrophils, a type of immune cell, can combat infection by expelling threads of “sticky” DNA full of antimicrobial compounds from inside the cell. The threads act like a spider’s web to ensnare and kill bacteria. These complexes are known as neutrophil extracellular traps or NETs. While this process forms an important part of the body’s defence against infection, NETs can also mistakenly kill the body’s own cells, leading to immune disease.
Dr Bruestle and her team had developed a new drug that neutralises NETs and found that blocking the NETs could prevent disease from developing in laboratory models of MS. This is very promising as the treatment has minimal side effects and is inexpensive to manufacture.
Following from these original findings, the aim of this project was to define how NETs cause inflammation in the brain in these models and how the new drug prevents this. Further, to begin to understand whether this may have potential as a therapy, the team investigated whether neutrophils and NETs are altered in people with MS.
In the first year of this project, Dr Bruestle’s team established a technique to visualise the cells that produce NETs under the microscope. This allowed the team to track the NETs and their production within the brain at various timepoints during disease in a laboratory model of MS and determine interactions between immune cells and the NETs.
Armed with these techniques, the team has now defined molecular mechanisms by which NETs interact with the immune system to cause inflammation in the brain. They identified that a particular component of the NETs, a series of proteins known as histones, are key to the inflammation caused. These proteins within NETs directly promote the development of a particular type of T cells (called “Th17”) that are known to be major drivers of neuroinflammation, and this team’s new drug can inhibit this process.
In addition, NETS have potent effects on the immune cells of the brain- the microglia. At lower levels, NETs activate the microglia, driving inflammation. At higher levels, NETs kill the microglia.
Moving to human studies, the team found that detection of NETs in blood with standard methods was not a feasible approach for the clinic, so they devised a new method for this detection. This novel method has enabled new collaboration and attracted additional funding towards developing handhold devices to detect NETs in real time in the clinic. The potential to use NETs as “biomarkers” for predicting when relapses will occur is still under investigation and planned future studies will address this.
The team also found that function of the immune cells which produce NETs, neutrophils, were strikingly different in people with MS who are undergoing treatment compared to those who are not treated, as well as in comparison to those who do not have MS. In addition, people with progressive MS have higher levels of neutrophils with changes in the number of various different kinds of neutrophils.
The funding of this initial project led to an $1.2 million industry funding package, a $300,000 philanthropic grant, and key participation in the $10 million initiative, “Our Health in Our Hands” (OHIOH) at the Australian National University.
In addition, the results generated from this project supported extension of the original patent on the NET inhibitor drug to include treatment of autoimmunity and inflammation.
Dr Bruestle highlighted the importance of MS Research Australia Project funding in supporting not only these exciting research developments, but the development of leadership in MS research in Australia: “Overall, this funding allowed me to establish myself as recognised player in MS. Without this initial trust in my project and my capability to lead it, I would have not been as able to secure additional funding, become the MS lead of “OHIOH”, a Tall Poppy (award winner) and a successful supervisor and part of the MS research community in Australia.”
Updated: 24 June 2020
Updated: 02 March, 2017