Antibody Targeting IL-23 Eases MG Symptoms in Two Mouse Models
Appears to lower activation of proinflammatory Th17 cells in muscles, thymus
Treatment with an antibody targeting the interleukin-23 (IL-23) protein reduced symptoms and eased inflammation in mouse models of myasthenia gravis (MG), a study found.
Evidence suggested the antibody lowers the activation of T-helper 17 (Th17) cells — a cell family implicated in MG and other autoimmune diseases — in the muscle and thymus gland. It also prevented the activation of cells responsible for producing disease-driving antibodies in the thymus.
“We showed that inhibiting the IL-23 pathway had a beneficial effect on all the tissues involved in MG pathology [disease mechanisms],” the researchers wrote, noting that current therapies targeting these pathways may help MG patients.
The study, “Blocking interleukin-23 ameliorates neuromuscular and thymic defects in myasthenia gravis,” was published in the Journal of Neuroinflammation.
IL-23 is signaling molecule that works to activate T-helper 17 cells
Th17 cell activation is a known driver of autoimmune diseases, including myasthenia gravis. Specifically, Th17 cells promote inflammation and activate B-cells — the immune cells that produce the self-reactive antibodies responsible for MG symptoms.
IL-23 is a signaling molecule involved in Th17 cell activation. Previous research demonstrated that the IL-23/Th17 pathway is activated and drives inflammation in the thymus of MG patients positive for acetylcholine receptor (AChR) antibodies, the most common type of MG-driving antibody.
Of note, abnormalities in the thymus are observed in most MG patients, and thought to be directly linked to the development of MG attacks.
Blocking the IL-23 /Th17 signaling pathway could be a potential way of preventing these autoimmune attacks and easing disease symptoms.
Researchers in France investigated the therapeutic potential of an antibody designed to block IL-23 activity in two mouse models of MG.
The first model, called the experimental autoimmune MG (EAMG) model, is a classic disease model commonly used to test potential treatments.
Results showed that two weeks of IL-23 antibody treatment significantly eased MG symptoms in these mice, and almost completely eliminated them after four weeks.
Circulating blood levels of interleukin-17, an inflammatory molecule produced by Th17 cells, were elevated in the EAMG model. These levels were reversed with the IL-23 antibody’s use, suggesting a reduction in Th17 activation.
Blood levels of a certain type of disease-driving AChR antibody also significantly dropped after two weeks of treatment.
Muscle function and strength improved in mice given the antibody. Notably, levels of various cells and molecules involved in muscle regeneration also increased with treatment.
Still, “the detailed mechanism responsible for these effects remains to be further deciphered,” the researchers wrote.
Anti-IL-23 antibodies used to treat two other autoimmune diseases
Because the EAMG model doesn’t show evidence of thymus dysfunction — a key feature observed in MG patients — researchers evaluated the effects of the anti-IL-23 antibody in the NSG-MG mouse model.
In this model, thymus fragments from MG patients are engrafted onto mice with the goal of triggering thymic and muscle abnormalities similar to those seen in patients.
As with the EAMG model, antibody treatment significantly eased MG symptoms in the NSG-MG model.
Observed changes also suggested lower Th17 cell activation in the engrafted thymus tissue. Specifically, diminishment was seen in a range of inflammatory molecules that promote the development and activity of Th17 cells.
In line with those observations, levels of certain Th17 cell populations were depleted with treatment.
While the antibody did not reduce the signals that attract B-cells to the thymus in MG, evidence pointed to it reducing their activation, a process that might help to prevent the production of disease-driving antibodies.
Findings overall supported the potential of therapies targeting the IL-23/Th17 signaling pathways in treating MG.
“More, monoclonal antibodies that target the IL-23/T17 cell pathway are emerging as therapeutic tools to treat autoimmune diseases,” the researchers wrote.
In particular, anti-IL-23 antibodies are in clinical use to treat psoriasis and Crohn’s disease, two autoimmune conditions that mainly affect the skin and the bowel, respectively. These approved medications could be of benefit to MG patients, the team noted.
“A clinical study (based on medicine repositioning) that aims to investigate the potential effects of such therapeutic option for early-onset [AChR-positive] MG patients should be envisaged,” the researchers wrote.