BioWorld International Correspondent
LONDON - A mistake over how long cells were left in culture has serendipitously led to a new and simple mouse model for autoimmune inflammation of the heart.
The researchers who made the finding hope that they will now be able to analyze exactly what triggers that type of heart disease. They also predict that it will be possible to follow the same method to generate useful mouse models of other autoimmune diseases that affect humans - including Type I diabetes, arthritis and multiple sclerosis - as well as boost the success of tumor vaccination strategies.
Josef Penninger, director of the Institute of Molecular Biotechnology at the Austrian Academy of Sciences in Vienna, told BioWorld International: "Our new culture method turns dendritic cells, which are the master regulators of the immune system, from lambs into wolves."
He and his colleagues have patented their method of activating dendritic cells and are looking for partners to help them expand their work.
An account of the study appears in the November issue of Nature Medicine. It is titled "Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity."
Penninger, working with colleagues in Vienna, including his postdoctoral student Urs Eriksson (now assistant professor at the University Hospital of Basel in Switzerland), and with collaborators in Switzerland and Canada, set out to make a new mouse model of heart inflammation.
The team thought that dendritic cells might play a role in autoimmune inflammation because they process endogenous antigens and so might be able to activate T cells capable of recognizing self antigens as foreign.
They began by isolating dendritic cells from the bone marrow of mice, which they cultured for about a week in the presence of the major structural protein of heart muscle. They then manipulated the cells to activate two types of cell-surface receptors: the CD40 receptor, which is part of the adaptive immune system, and Toll-like receptors, which form part of the innate immune system.
They returned between 50,000 and 100,000 of the cells to the animals, which developed massive inflammation of the heart about a week later. Although that resolved within a couple of weeks, subsequently exposing the animals to an infection stimulus triggered a massive relapse of the heart inflammation.
Penninger said: "Our results show that the concerted action of innate and adaptive immunity on dendritic cells triggers autoimmune heart disease and heart failure following resolution of the heart inflammation. These data provide a direct link between autoimmune heart disease and the development of dilated cardiomyopathy and heart failure."
The "mistake" made by Eriksson, who left the cells to activate their receptors for only four hours rather than for 24 hours, as dictated by existing protocols, poses an intriguing question, Penninger said.
"We will be investigating why it is that when we turn on these receptors for a certain period of time, they behave like this and make the mice sick, whereas when we leave them to activate for longer, nothing happens," Penninger said. "We predict that these cells are either shutting down or making a cytokine or surface receptor, which breaks tolerance in a previously healthy animal."
The group would be studying that aspect using gene arrays, Penninger said. They also will set up drug screening to identify compounds able to interfere with the system and prevent the inflammation developing.
One exciting aspect of the study, Penninger added, is how it can provide a unifying theory to explain how tissue damage and infections can induce autoimmunity and autoimmune relapses in many different diseases.
"It can explain why there seems to be an association between infections and the development of diabetes - because infections trigger the Toll-like receptors," he said. "The reason no one can find the autoimmune' bug that triggers this must be because there is no single bug that does it. They can all do it."
The team expects other researchers working on autoimmune diseases to follow up their finding and make further animal models for other diseases. For example, giving the dendritic cells insulin or collagen could generate new animal models for diabetes and arthritis, respectively.
Finally, Penninger and his group are planning to explore how they can apply their highly activated dendritic cells to boost the effectiveness of tumor vaccines.
"It is not a new idea to take breast cancer cells, or melanoma cells, feed them to dendritic cells and then put the dendritic cells back into patients - but cancer researchers have told me that the problem is in obtaining enough cells to have an effect," Penninger said. "Perhaps if they activate them using our system, they will be able to improve the effectiveness of their therapeutic strategy."