In studying how mycophenolate mofetil treatment affects immune cells and blood markers in people with systemic lupus erythematosus (SLE), researchers uncovered an immune pathway that may explain why is lupus suppressed by this medication.
Their findings might also aid doctors in making treatment decisions.
Led by scientists at Oklahoma Medical Research Foundation (OMRF), the study “Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients” was published in the journal JCI Insight.
“One of the biggest challenges we face in treating lupus is that we do not have any medications that work without side effects for every single patient,” Judith James, MD, PhD, OMRF’s vice president of clinical affairs and the study’s senior leader, said in a press release.
“We need to better understand why some medications work for some patients and not others — without having to go through a trial-and-error process,” she added.
With that aim in mind, James and her team focused on SLE patient response to mycophenolate mofetil (MMF; brand name CellCept, by Genentech), an immunosuppressive medication often used in combination with other agents to prevent organ rejection after a transplant. It also prescribed to SLE patients with potentially serious complications, like involvement of the kidneys, brain, or multiple organs.
Due to its effectiveness and safe profile regarding side effects, MMF is now considered a standard treatment for lupus nephritis (kidney inflammation caused by lupus), while studies continue to determine its usefulness for other manifestations.
However, the immune pathways (cells, messenger molecules) associated with disease suppression by this treatment remain poorly understood.
To identify molecular clues that might help to explain why MMF works against lupus, researchers looked at which immune cells and blood markers changed in five SLE patients using MMF in comparison to 10 not taking it.
They saw that MMF was preventing the activation of a factor called STAT3, as well as inducing changes in its associated immune pathways.
STAT3 is a transcription factor that when active, commands certain genes to be turned “on.” It plays a critical role in several cellular processes, including cell growth, cell movement, and cellular self-destruction (apoptosis).
In the immune system, STAT3 transmits signals for the maturation of immune cells, especially T- and B-cells, and is involved in regulating inflammation.
That is why too much STAT3 or its excessive activation are linked with different autoimmune conditions and cancer.
Researchers also saw that SLE patients on MMF had less STAT3 that was active, which was associated with lower total numbers of certain immune cells, namely some types of B-cells, plasmablasts, and T-cells, compared to patients not using MMF.
Other immune-related signaling mediators were also lower in MMF-treated patients, including the chemokines (signaling molecules that control immune function) CXCL9 and SDF-1α, and growth factors VEGF-A and PDGF-BB.
Taken together, these changes revealed significant modifications associated with STAT3 and B-cell pathways.
Experiments in blood cells cultured in the laboratory confirmed these findings. Immune cells treated in the lab with mycophenolic acid, the active form of MMF, had less active STAT3.
“In conclusion, the inhibition of STAT3 [activation] by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of [active STAT3] are associated with disease pathology,” the researchers wrote.
“These data hold promising information for drug therapy development utilizing MMF and associated pathway inhibitors,” they added, recommending that larger studies explore in more detail how STAT3 is inhibited by MMF.
“This is giving us new clues as to how MMF works in specific patients by seeing what the immune system does both on and off it,” said Joel Guthridge, PhD, immunologist at OMRF and a collaborator in the study.
Researchers also suggest these results could help guide doctors in treating a patient, bringing them closer to personalized treatment solutions, the release states.
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