Blocking a key inflammation molecule in the immune system’s T helper cells could be a first step to developing new treatments to eradicate multiple sclerosis (MS) and other autoimmune diseases, said researchers who wrote about their discovery in Nature Immunology this week.

An inflammatory cytokine in T helper cells called granulocyte-macrophage colony-stimulating factor, or GM-CSF for short, appears to be a driving force behind autoimmune diseases, said study leader Dr Abdolmohamad Rostami, professor and chairman of the Department of Neurology at Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania, USA, and colleagues.

The immune system comprises an array of cells, processes and molecules that detect and respond to foreign agents, pathogens and injury to prevent harm and restore health, but in autoimmune diseases these attack healthy tissue instead.

For their study, Rostami and colleagues focused on a group of immune cells called T helper 17 cells (Th17), which normally protect cells against invasion by pathogens, but are also known to be involved in autoimmune diseases in humans and animal models, although the mechanisms involved are somewhat of a mystery.

In their study, the team showed that GM-CSF could be a key culprit in the onset of MS, because without it, Th17 cells did not induce MS-like disease in an experimental animal model.

Rostami told the press that their study is the first to show a link between GM-CSF and Th17 cells:

“What we have shown in this paper is that GM-CSF derived from Th17 cells is important in the cell-signaling process that leads to inflammation in the central nervous system,” he explained.

Blocking this cell-signaling molecule could be a first step to developing new treatments to eradicate MS and other autoimmune diseases, said Rostami, who is also the Chair of Neurology at Thomas Jefferson University Hospital.

The team discovered that a pathway described as the Interleukin-23 (IL-23)/ Th17/GM-CSF axis is the main route to development of inflammation in the central nervous system in autoimmune diseases like MS.

IL-23 is a cytokine, a signalling molecule, that is already known to cause autoimmune inflammation in the brain (it is encephalitogenic), and the researchers found that when exposed to it, Th17 cells produce more GM-CSF.

They bred mice with autoimmune encephalomyelitis (EAE), a common animal model used in to study the biology of MS.

They found that mice whose Th17 cells could not produce GM-CSF did not go on to develop neuroinflammation, showing GM- CSF to be the cause of the disease in the animal model.

They also found a feedback loop whereby secretion of GM-CSF by Th17 “stimulated the production of IL-23 by antigen-presenting cells”.

“Such cross-regulation of IL-23 and GM-CSF explains the similar pattern of resistance to autoimmunity when either of the two cytokines is absent and identifies TH17 cells as a crucial source of GM-CSF in autoimmune inflammation,” they wrote.

In a paper published in an earlier issue of the journal, Rostami and his team described how they discovered another related mechanism in MS where another cytokine, Interleukin-27 (IL-27), helped block, but did not induce, the onset of symptoms in animals with an MS-like disease.

Bringing the results of the two papers together, the researchers suggested that while increasing levels of GM-CSF may cause MS, increasing IL-27 may help quell an overactive immune system.

Rostami said of the earlier paper:

“That was the first time that we had direct evidence that by actively giving IL-27 like a drug, we can suppress EAE in mice.”

Rostami said if what their recent paper suggests about GM-CSF’s role can be found in human blood samples, it may be possible to start looking for a new treatment for MS:

“If we can try to neutralize GM-CSF by different means, for example, by trying to mimic it or trying to block the receptor for GM-CSF, we can hopefully ameliorate the disease,” said Rostami.

“The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM- CSF.”
Mohamed El-Behi, Bogoljub Ciric, Hong Dai, Yaping Yan, Melissa Cullimore, Farinaz Safavi, Guang-Xian Zhang, Bonnie N Dittel, Abdolmohamad Rostami
Nature Immunology Published online 24 April 2011.
DOI:10.1038/ni.2031

Additional sources: Thomas Jefferson University, eBioscience.

Written by: Catharine Paddock, PhD