Research breakthrough provides clues for Lupus treatment
Many medications treat more than one condition. People pop aspirins to allay headaches and heart disease. Doctors prescribe antidepressants to alleviate both mood and gastrointestinal disorders. Now Drs. Chongmin Huan and Christopher Roman at the SUNY Downstate Health Sciences University have received a TAF grant to investigate a compound, that is also being tested for potential treatment of brain cancer, for use as a drug to potentially treat systemic lupus erythematosus (SLE), or lupus.
Lupus is an autoimmune disease, whereby the patient’s immune system attacks his or her own tissues and organs. It’s painful and dangerous, possibly causing kidney failure, stroke, and heart attacks.
Using the drug to treat lupus was hardly an obvious jump. “That took smart and logical deductive reasoning, a flash of insight, and a thoughtful literature review,” says Dr. Roman, Associate Professor and Vice Chair of Cell Biology and Medicine and a co-PI in the study. In fact, it took a lot more than that—the scientists’ flash of insight was based on a unique discovery they made about an unforeseen pathway in the immune system.
Their journey began when they were working with knockout mice that had a mutation in a gene that controls a particular pathway in fat metabolism. To their surprise, they found that these mice also displayed a lupus-like autoimmune disease. Being scientists, they proceeded to investigate the underlying connection and discovered a lipid enzyme that fulfills two functions: It directly controls fat metabolism while also controlling a second, distinct enzyme that prevents lupus.
“We looked at our mice and the mechanism behind what was going on and said, ‘Hey, besides regulating lipid metabolism, this enzyme actually controls another enzyme that is well known to prevent lupus disease,’” says Huan, Assistant Professor, Director of Surgery Research in the Departments of Surgery and Cell Biology, and lead scientist on the study.
But that was only the beginning. What, the scientists wondered, did their discovery reveal anything about the way the healthy immune system works? And what might it reveal about what goes wrong in individuals with autoimmune diseases like lupus?
The human immune system has a wonderful self-protective mechanism. Cells produced in the bone marrow, called B cells, produce antibodies to fight foreign invaders like bacteria and viruses. A process called somatic hypermutation enables B cells to mutate and produce even more effective antibodies. There’s a hitch in the system, though: mutation is random, so in addition to generating B cells that produce super effective antibodies, it also generates dangerous B cells that produce antibodies that attack the victim’s own body rather than foreign invaders.
Most of these dangerous B cells are weeded out at checkpoints in the bone marrow, spleen, and lymph nodes. “In healthy people, those self-reactive dangerous B cells are eliminated, but that seems to fail, or is severely impaired, in individuals with lupus,” says Dr. Roman.
That’s where the dual-function lipid enzyme comes in. The team composed of a PhD candidate, Ms. Peiqi Ou, a pathologist, Dr. Stanek and Drs. Huan and Roman conducted further studies with mice spontaneously born with lupus, they measured the activity of the main component in the immune system’s self-protective mechanism. They found that administering an oleic acid derivative —the active ingredient in the compound tested for brain cancer—stimulates the dual-function enzyme to command the dangerous B cells to kill themselves. For reasons that are still being worked out, this pathway does not get activated for healthy B cells.
So, there it was: a compound that could seemingly trigger the destruction of autoimmune-causing B cells while leaving the beneficial B cells intact.
To treat lupus, the proposed therapy will improve on current lupus therapies in the US in a number of ways. First, most current therapies for lupus work by suppressing the entire immune system, including the B cells that keep us healthy. The proposed therapy, on the other hand, could selectively inhibit only the self-reactive B cells. A currently available antibody-based drug called belimumab works by targeting a different pathway in the immune system, but it can only be administered by injection. The oleic acid derivative, on the other hand, is orally available, which makes it far easier for patients to use.
The research team has already tested the drug on a small number of lupus and non-lupus mice. They’ll use the $45K they received in TAF funding for additional animal studies, as well as other experimental modalities, in collaboration with Drs. Ginzler and Dvorkina, two well-known rheumatologists at Downstate. “We’ll get some normal human B cells from a blood bank, and we will also harvest some lupus patient blood B cells to test the protective mechanism and molecular pathway in those cells,” says Dr Huan.
If successful, the drug will treat lupus. But there’s another serious challenge to health that the drug will address: a social injustice known as healthcare inequity.
According to the Lupus Foundation of America, people of African, Asian, and Native American descent are more likely to develop lupus than Caucasians are. They also report that 90% of people diagnosed with the disease are women, most often of childbearing age. Against that statistic, the National Academy of Medicine (NAM) reports that racial and ethnic minorities receive lower-quality health care than white people, even when income and insurance status are comparable.
Creating a therapeutic that can vastly ameliorate the health of underserved communities plays a big part in the pride Drs. Huan and Roman take in their work. Says Dr. Roman, “We know how horrible and devastating a disease like lupus is. It primarily affects young women at the prime of their lives, it typically affects women in their early 20s, and it disproportionately affects women of color. It's a devastating disease that’s additionally burdened by social determinants of health and disparities. Just to find a new path to a better treatment is very gratifying to both of us, because we know firsthand how limited the tools to treat it are.”
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