In a patient with the autoimmune disease lupus, immune cells attack the body’s own tissues as if they were an invading pathogen. This can lead to damage to the skin, joints, kidneys, and even the brain.
Now a team of immunologists reports that some of these errant immune cells have an overactive metabolism, and that inhibiting two key metabolic pathways can reverse lupus symptoms in mice (Sci. Transl. Med. 2015, DOI: 10.1126/scitranslmed.aaa0835).
The study provides compelling evidence that a combination of metabolic inhibitors could be an effective lupus therapy, say Manan M. Mehta and Navdeep S. Chandel of Northwestern University in a perspective they wrote about the study.
Before testing these inhibitors, Laurence M. Morel at the University of Florida and her colleagues first studied the metabolism of CD4+ T cells. In lupus, the immune cells command B cells to produce autoantibodies, which target the body’s own tissue.
When T cells are on the hunt for pathogens, they ramp up their metabolism so they can proliferate quickly. Morel hypothesized that in lupus patients, overly aggressive T cells would also have an overly active metabolism.
To test the idea, the researchers looked at two pathways involved in glucose metabolism: glycolysis and oxidation that occurs in a cell’s energy-generating mitochondria. Compared with T cells from healthy mice, lupus cells had lower pH levels and consumed more oxygen, signs of high rates of glycolysis and mitochondrial oxidation, respectively.
Morel and her team then tested two metabolic inhibitors on lupus mice: 2-deoxyglucose, which inhibits glucose metabolism, and metformin, which slows electron transport in the oxidation pathway in mitochondria. Lupus mice that received the two compounds in their drinking water showed a reversal of symptoms over three months. Levels of autoantibodies dropped, kidney health improved, and T-cell activation returned to normal.
Metformin is already approved by the Food & Drug Administration for treating type 2 diabetes, but Morel says she needs to collect more data on the inhibitors and their effects on the immune system before starting a clinical trial in lupus patients.