May 22, 2019
Data presented by several Lupus Research Alliance-funded scientists at the recent American Association of Immunologists Annual Meeting suggests many avenues for new lupus treatments. Some scientists presented data posing new targets for drug development, while others have discovered cells that suppress the immune response and could be harnessed as treatments.
Reining in B Cells
The immune cells known as B cells are harmful in lupus because they produce proteins called antibodies that attack patients’ own tissues. New findings from Drs. Hui-Chen Hsu and John Mountz at University of Alabama at Birmingham may explain how harmful B cells live in the body and offer a new way to reduce their numbers. Dr. Hsu is a Novel Research Grant awardee, and Dr. Mountz received the 2017 Dr. William E. Paul Distinguished Innovator Award.
Like a car on the assembly line, maturing B cells must pass several quality control checkpoints where faulty cells that could launch attacks against patients’ tissues are weeded out. Drs. Mountz and Hsu and their colleagues found that in people with lupus, faulty B cells may slip past these checkpoints. Some patients in which one checkpoint failed, produced too much of the immune molecules called type I interferons. The researchers also found a second checkpoint in which high levels of a cytokine receptor acts to stop development of B cells. It was proposed that blocking type I interferons pathways and increasing signaling by stopping pathways would better control these B cells.
Other findings from the Hsu/Mountz team suggest a way to prevent development of the immature B cells that ‘grow’ to become one of the main sources of harmful antibodies in patients with lupus. The scientists studied which genes were active in these cells. One of the genes they found, TNFR2, could be a target for new drugs to stop the immature cells from forming and reproducing.
B cells don’t start making damaging antibodies unless they are stimulated by other immune cells called helper T cells. A third study from Drs. Mountz and Hsu and their colleagues suggested that to reduce the production of antibodies, treatments will have to block two kinds of helper T cells. The drug ustekinumab (Stelara®) may do just that and is being tested in a phase 3 clinical trial for lupus patients. Stelara® is already approved by the U.S. Food and Drug Administration (FDA) for certain other autoimmune diseases. This trial is being conducted through the Lupus Research Alliance’s Lupus Clinical Investigators Network (LuCIN), a network of academic centers formed to accelerate drug development. LuCIN is administered by Lupus Therapeutics, an affiliate of the Lupus Research Alliance.
New Insights on Regulatory Cells
A potential treatment approach for lupus involves so-called regulatory cells in our bodies that put the brakes on the immune system. Dr. Vipin Kumar of the University of California, San Diego, recipient of a Novel Research Grant, and his colleagues demonstrated a novel way to activate one type of regulatory cell and identified a new variety of the cells that could be harnessed to treat lupus.
Dr. Kumar and his team have been investigating whether miltefosine, a drug approved by the FDA for a rare tropical disease, is effective against lupus nephritis, the kidney inflammation common in patients with lupus. The researchers discovered that the drug stimulates one type of regulatory cell known as type II natural killer T cells. In a mouse model of lupus, miltefosine reduced the amount of kidney damage, suggesting it might help patients with the disease. Researchers hope to begin clinical trials of miltefosine for lupus in the near future.
The scientists also discovered a new type of regulatory cell, known as uTr cells, in the liver. The cells protected mouse models from two diseases in which the immune system attacks the body’s tissues, multiple sclerosis and colitis; researchers believe they could do the same in lupus.
Possible Drug Target for Lupus Nephritis
The immune molecule GM-CSF is a culprit in many autoimmune diseases because it promotes inflammation. Dr. Xian “John” Zhang of the Medical University of South Carolina in Charleston, recipient of a Novel Research Grant, and colleagues have demonstrated that the protein Fli-1 spurs cells to make GM-CSF. They found that Fli-1 causes kidney inflammation in mice, while reducing the protein levels in human kidney cells curbs their production of GM-CSF. Those results make Fli-1 a potential target for new drugs to treat lupus nephritis, Zhang says.
Although these discoveries require further study, each could open the way for new lupus treatments.