Spotlight on Research for 2003

November 2003 (historical)

Specific Cellular Interactions Can Be Blocked in Lupus

Researchers have found a way to reduce disease activity in people with lupus nephritis by blocking contact between lymphocytes. Lupus nephritis is a form of kidney inflammation that can lead to kidney failure. The researchers were able to relieve symptoms in some study participants and send the lupus nephritis into remission in others who received longer courses of treatment. Lupus, also called systemic lupus erythematosus or SLE, is an autoimmune disease in which the B lymphocytes, white blood cells that secrete antibodies, are hyperactive and target healthy tissues by mistake.

The findings, featured on the cover of the November 15 issue of the Journal of Clinical Investigation, offer hope that the autoimmune reactions of lupus may one day be prevented. The work was conducted by Amrie Grammer, Ph.D., Peter Lipsky, M.D., and Gabor Illei, M.D., of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), as well as other researchers at the National Institutes of Health (NIH) and other institutions.

Previous laboratory experiments showed it was possible to interrupt the interactions between cells that cause an autoimmune reaction. The investigators wanted to find out whether they could reproduce those results in lupus patients. They recruited six volunteers with lupus nephritis. These volunteers had previously participated in NIAMS clinical trials studying the natural history of lupus nephritis with standard treatment. Investigators treated the volunteers with an antibody that was created to interfere with cell interactions, specifically, interactions between one protein, CD40, and another, CD154. The antibody, developed in mice, was humanized; that is, it was designed to mimic human antibodies so that the volunteers' immune systems wouldn't attack it and render it useless.

To find out if the interactions had been blocked successfully, the investigators conducted extensive tests of B lymphocytes in the participants' blood before and after treatment. The researchers observed a significant decrease in the activity of B lymphocytes and the number of antibody-secreting plasma cells, both of which indicate disease activity in lupus, after treatment. Also, the volunteers experienced relief of symptoms.

The trial was stopped when some of the participants developed blood clots, which may be related to underlying vascular disease in certain patients. Dr. Lipsky states, "This trial was conducted using a small number of patients. We'll need to do larger, comprehensively controlled clinical trials to determine a safe and effective means to block these vascular side effects."

The idea to interrupt these cell interactions occurred to the investigators eight years ago while doing laboratory research. At that time, Drs. Grammer and Lipsky determined that B lymphocytes express the CD40-ligand molecule, also called CD154. This ligand attaches to a certain protein on another cell, which is called the cell-surface receptor CD40. A ligand on one cell and a receptor on another will fit together, or bind, like a lock and key. Once CD154 (ligand) binds CD40 (receptor) on another cell, the interaction signals the body to make antibodies that bind invading organisms and ultimately destroy them. In lupus patients, the B lymphocytes are hyperactive, creating antibodies that bind healthy cells by mistake and thereby destroy healthy tissues. Dr. Grammer says, "These clinical findings are consistent with the published preclinical laboratory studies and suggest that CD154-CD40 interactions are a central target of therapy in SLE."

Stephen I. Katz, M.D., Ph.D., director of the NIAMS, says, "This is exactly what translational research is all about, taking what we learn in our labs and translating it into treatments which benefit people with diseases. I look forward to hearing much more about their progress."

Lupus is often called an antibody-mediated disease, which means it occurs when the body makes antibodies towards itself. It can affect many parts of the body, including the joints, skin, kidneys, heart, lungs, blood vessels and brain. Some of the most common lupus symptoms include extreme fatigue, painful or swollen joints (arthritis), unexplained fever, skin rashes and kidney problems. Many more women than men have lupus. It is three times more common in African American women than in Caucasian women, and it is also more common in women of Hispanic, Asian and Native American descent.

NIAMS is a part of the Department of Health and Human Services' NIH. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov.

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Grammer AC, et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. Journal of Clinical Investigation 2003;112(10):1506-20.