Researchers in the United Kingdom have uncovered new details of key immune-signaling molecule interleukin 2 (IL2), raising hopes for improved clinical outcomes and reduced side effects from the otherwise promising treatment.
IL2 is involved in multiple communication networks in the immune system, is produced by a variety of cellular sources, and affects a diversity of cell responders. The protein is not only needed for maintaining regulatory T cells, which prevent our body’s immune system from attacking itself, but also CD8 T cells, which attack tumor cells and virus-infected cells. But despite being actively explored in hundreds of ongoing clinical trials, the full therapeutic potential is currently limited by frequently encountered side effects.
According to Dr. Carly Whyte, a postdoctoral researcher in the Babraham Institute lab of Adrian Liston, IL2 is normally tightly regulated in the immune system because it has such strong effects. “However, when IL2 is given as a therapeutic treatment, these normal restrictions on IL2 are overruled,” Whyte says. “By using mouse models, we have found that the presence of IL2 in certain zones of the immune system leads to some of the same side effects that we see in human patients treated with IL2. We hope that by understanding more about how IL2 works in different zones, this treatment might be tailored to be more effective." The mouse model in question is new and allowed the research team to control which immune cell types produced IL2.
Previous explanations for these side effects were based on the high doses of IL2 when given as a biologic drug, but Liston and his team were able to demonstrate that the cell type making IL2, and the location of those cells, dramatically change the consequences of IL2 exposure.
"Our genetically modified mouse models showed that the immune responses are varied depending on the source of IL2,” says coauthor Dr. Kailash Singh. “Our findings revealed that the IL2 response is very much context-dependent, and is not solely due to the concentration of IL2."
Dr. James Dooley, joint senior author of the study, says the work demonstrates that one route of smart design of IL2 is to target delivery to different parts of the body, “potentially allowing us to drive very different therapeutic outcomes in patients."
The findings were published recently in the Journal of Experimental Medicine.