A recent study has revealed details of how a compound that improves lupus-like kidney disease in mice specifically targets and kills certain disease-causing white blood cells. The results of the study by Gary Glick, PhD, Anthony Opipari, Jr., MD, PhD, and their colleagues at the University of Michigan in Ann Arbor support ongoing efforts to develop drugs related to this compound for treating lupus nephritis (kidney disease). Dr. Glick has a grant from the Alliance for Lupus Research (ALR) to help develop such drugs for testing in humans. The new study was published online by the Journal of Biological Chemistry on May 3, 2004, in advance of print publication.
In previous studies, Dr. Glick and his coworkers identified a new compound that kills B cells—white blood cells that are thought to play a key role in systemic lupus erythematosus (SLE, or lupus). They found that this compound, called Bz-423, improves kidney disease in two strains of mice that develop lupus-like illnesses. In addition, says Dr. Glick, “we demonstrated that—unlike current drugs for lupus—Bz-423 is very selective for autoimmune processes versus normal immune processes” in mice. In particular, Bz-423 killed disease-causing B cells in lupus-prone mice but did not affect white blood cells in normal mice when given in the same doses. The goal of the new study was to figure out why Bz-423 has such selective effects on disease-causing B cells.
Through experiments with B cells grown in the laboratory, the researchers found that activated B cells are more sensitive to killing by Bz-423 than resting B cells. Activation of resting B cells “is one step on the pathway to making a B cell that will secrete antibodies,” explains Dr. Glick. In lupus, B cells are activated inappropriately, leading to the production of disease-causing autoantibodies that attack the body’s own healthy tissues. These autoantibodies are produced by long-lived circulating cells that develop from activated B cells in areas of the body known as germinal centers. And, says, Dr. Glick, “we’ve gone on further to show that it’s not just all activated B cells but the activated germinal center B cells in particular that are more sensitive to Bz-423.”
What it means for people with lupus: Together with their earlier studies, the recent findings by Drs. Glick, Opipari, and colleagues suggest that compounds related to Bz-423 “not only are going to be effective against lupus nephritis, but also are likely to be very specific, with the potential for far fewer side effects” than current treatments, Dr. Glick says. Although Bz-423 is effective, it has some chemical properties that would make it hard to use as a drug in humans. Dr. Glick has a grant from the ALR to develop a compound that is chemically related to Bz-423 and is suitable for human use—in particular, a drug that could be given in pill form. He and Dr. Opipari are also working with a startup company to develop related compounds for treating lupus nephritis as well as other autoimmune diseases. Further development and testing are needed to find out whether these compounds will indeed be safe and effective treatments for lupus nephritis.
To read more on the latest in lupus research, click here to download the most recent Lupus Research Update.
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