White blood cells known as B lymphocytes, or B cells, play a central role in the development of systemic lupus erythematosus (SLE, or lupus). B cells, which are a crucial part of the immune system, normally produce antibodies that defend against infection by bacteria and viruses. But in people with lupus, some B cells produce abnormal antibodies (called autoantibodies) that react against the body’s own healthy cells and tissues, contributing to inflammation and tissue damage. In addition to producing autoantibodies, says Alliance for Lupus Research (ALR) investigator Robert Eisenberg, MD, of the University of Pennsylvania, “B cells probably play other important roles in this disease, based on their additional functions in immune regulation and secretion of inflammatory mediators.”
According to ALR Scientific Director John H. Klippel, MD, “Recent scientific advances in understanding B-cell biology in lupus point to the importance of genetic factors and alterations of signaling pathways in the B cell that may be responsible for lupus. More importantly, these scientific advances are leading to new therapeutic strategies targeting the B cell, some of which are already in clinical trials.” This issue of the Lupus Research Update highlights several potential strategies for treating lupus that target B cells.
Recent preliminary studies suggest that rituximab, a drug known to deplete B cells, is safe and may be effective for treating lupus. Maria Leandro, MD, and her colleagues at University College in London published results of one such study in the October 2002 issue of Arthritis and Rheumatism. They found that five out of six women with severe active lupus showed improvement in various signs and symptoms of disease 6 months after treatment with intravenous rituximab combined with intravenous cyclophosphamide (Cytoxan®) and high-dose oral corticosteroids, both of which are currently used to control symptoms of lupus. The treatment was well tolerated, with no major adverse effects.
Rituximab is a genetically engineered antibody that targets a protein known as CD20, which is found on the surface of all B cells. “In patients, rituximab is highly effective in depleting B cells from the circulation,” says Dr. Eisenberg, who is developing mouse models of B-cell depletion with support from ALR.. Rituximab has been used for several years to treat B-cell lymphomas, and has been shown to be relatively safe. Although doctors feared that depleting B cells would weaken the immune system and render people susceptible to repeated bacterial infections, Dr. Eisenberg says, “clinical evidence so far does not support that concern.”
“It’s time to do a proper controlled trial to prove whether rituximab works or not” as a treatment for lupus, Dr. Eisenberg says. He and his colleagues Dan Albert, MD, at the University of Pennsylvania and John Looney, MD, of the University of Rochester are currently working on a protocol to evaluate rituximab in patients with lupus kidney disease and a high chance of progressing to renal failure. Patients in the study would be treated with Cytoxan, which is the usual treatment for lupus kidney disease, or Cytoxan plus rituximab. Dr. Eisenberg and his colleagues are also planning a controlled trial of rituximab in lupus patients with severe skin manifestations resistant to current treatments.
A new compound that targets B cells and is a chemical cousin of anti-anxiety medications such as Valium and Xanax may also hold promise for treating lupus, according to an article in the October 15, 2002 issue of the Journal of Immunology. Researchers led by Gary Glick, PhD, of the University of Michigan, identified a compound called Bz-423 that causes B cells to undergo a natural process of cell suicide. The body normally uses this cell-suicide process to rid itself of unwanted or potentially harmful cells, including B cells that could attack healthy tissues in the body. But in lupus this process appears to be impaired, allowing disease-causing B cells to survive.
The researchers tested Bz-423 in mice that develop a lupus-like illness as a result of aberrant B-cell survival and autoantibody production. At the end of a 12-week treatment period, 60 percent of untreated mice had developed moderate or severe kidney disease, compared to only 16 percent of treated mice. The mice treated with Bz-423 showed none of the serious side effects caused by powerful cell-killing drugs currently used to treat lupus.
ALR investigator Robert Carter, MD, of the University of Alabama at Birmingham, notes that Bz-423 is particularly interesting because it appears to preferentially cause the death of “activated” B cells, which are primed to produce autoantibodies. “We don’t know why B cells get activated in lupus, but they do,” Dr. Carter says. “The hope would be that this drug could target the B cells that are activated in lupus, without eliminating B cells that can respond to any infectious agents you might encounter.” Unlike Valium and related drugs, Bz-423 does not cause drowsiness or addiction, according to Dr. Glick. Furthermore, he says, the fact that so much is already known about this group of drugs should help in moving the new compound to clinical trials in people with lupus.
A study published in the September 16, 2002 issue of the Journal of Experimental Medicine describes another approach aimed at B cells that slows the development of lupus kidney disease in mice. Ram Raj Singh, MD, and Guo-Chang Fan, PhD, of the University of Cincinnati College of Medicine developed a vaccine that leads to elimination of autoantibody-producing B cells in mice. The vaccine contains a “minigene” (a piece of DNA) that cause mouse cells to start making snippets of proteins that are found in certain autoantibodies in lupus-prone mice but are uncommon in normal antibodies. These snippets trigger the action of immune cells known as killer T cells. The killer T cells appear to selectively destroy autoantibody-producing B cells in the mice, while sparing normal B cells.
Vaccination of lupus-prone mice with the minigene slowed the development and progression of kidney disease and prolonged survival compared to unvaccinated mice. The vaccinated mice also had reduced levels of autoantibodies in the bloodstream. According to the researchers, “this approach of inhibiting autoantibody production may pave the way forÉspecific treatments for patients with SLE.”
What these studies mean for people with lupus: New approaches that target B cells in people with lupus offer hope for more effective treatments with fewer side effects. “A strategy that selectively eliminates B cells is a big step forward,” Dr. Carter states. Such treatments should provide a significant advantage over less specific drugs now used to treat lupus, which kill healthy cells in the body along with B cells and other immune cells and can have serious side effects, particularly when taken for long periods.
Research supported in part by a grant from ALR to William Stohl, MD, PhD, of the University of Southern California has revealed new information on B-cell biology that could lead to treatments that selectively target disease-causing B cells in lupus. Dr. Stohl and researchers from Human Genome Sciences, in Rockville, Maryland, found that two related molecules important for B-cell function, known as B lymphocyte stimulator (BLyS, pronounced “bliss”) and APRIL, bind together in a complex that can stimulate B-cell activity. They also found elevated blood levels of these BLySAPRIL complexes in people with lupus and other autoimmune rheumatic diseases, as reported in the October 15, 2002 issue of the Journal of Immunology.
A link between BLyS and lupus in humans was previously reported by Tong Zhou, MD, an investigator on Dr. Carter’s ALR-funded project at the University of Alabama (UAB), with ALR Scientific Advisory Board member Robert Kimberly, MD, also of UAB, and by Dr. Stohl’s lab. Their work suggests that higher than normal BLyS levels in people with lupus may contribute to autoantibody production and disease development. Previous research showed that BLyS is required for the survival of most B cells. In addition, laboratory studies in mice showed that increased BLyS levels cause a lupus-like illness, and that eliminating BLyS causes most normal B cells to disappear. On the basis of these and other findings, Human Genome Sciences has begun a clinical trial of LymphoStat-B, a laboratory-produced antibody that binds and neutralizes circulating BLyS, to test its safety and learn about its properties in people with lupus.
Meanwhile, the new findings show that BLyS does not always act alone. Scientists knew that complexes made up of three BLyS molecules or three APRIL molecules existed, but they did not know that mixed complexes of BLyS and APRIL also occur and can activate B cells. Furthermore, the results indicate that the BLyS-APRIL combination may have different or more limited effects on B cells than does BLyS alone. In addition, “the form that has both BLyS and APRIL shows the most dramatic increase in people with autoimmune diseases,” says Dr. Carter, who has a grant from ALR to study the role of these molecules in lupus.
What it means for people with lupus: Better understanding of the different roles of BLyS and APRIL in lupus may open the door to “second generation” therapies that selectively target only certain actions of these molecules, which is the goal of work Dr. Carter is doing with support from ALR. These second-generation treatments might be able to eliminate disease-causing B cells without eliminating all other B cells, thereby preventing the body from losing the immunity it has built up against bacteria, viruses, and other harmful substances to which it was exposed in the past.
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