Gene Replacement Prevents Lupus-Like Autoimmune Disease in Mice

NATIONAL INSTITUTES OF HEALTH	National Institute of Arthritis and Musculoskeletal and Skin Diseases
March 14, 1994	Contact: Elia Ben-Arii Office of Scientific and Health Communications (301) 496-8188

Researchers have found that replacing a single defective gene can correct a lupus-like autoimmune disease in mice. The gene, called lpr or Fas , plays a key role in a process known as programmed cell death or apoptosis. Apoptosis enables the body to eliminate unnecessary, damaged, or potentially harmful cells. This research may open the door to new treatments targeted to specific defects in lupus.

"Before this cure was engineered in mice, it was unclear that this single gene could account for many of the problems of an autoimmune disease," says lead researcher Dr. John D. Mountz of the University of Alabama at Birmingham, whose findings are reported in the March 15 issue of Proceedings of the National Academy of Sciences . "The development of many autoimmune diseases involves the concerted influence of several genes," says Dr. Susana Serrate-Sztein. "The beauty of these results is that they show that if you know what the most important gene defect is, gene therapy or other treatments that correct that specific defect may be feasible for diseases like lupus. A lot of effort is being spent in identifying those genes in humans," says Serrate-Sztein, Chief of the Rheumatic Diseases Branch at the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

This research was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a component of the National Institutes of Health (NIH), as well as by NIH's National Institute of Allergy and Infectious Diseases and the Department of Veterans Affairs.

In the immune system, apoptosis is responsible for eliminating white blood cells with the potential to attack the body's own tissues. Normally, the immune system detects these "self-reactive" cells, and they are destroyed by apoptosis before they can do any harm. If apoptosis is defective, self-reactive cells will survive and may cause autoimmune diseases such as lupus. Some of these white blood cells produce autoantibodies--antibodies directed against the body's own cells and cell components.

Lupus is characterized by inflammation that causes redness, pain, swelling, and tissue injury in different parts of the body. These include the joints, skin, kidneys, lungs, heart, nervous system, and blood vessels. The signs and symptoms of lupus differ from one person to another, and the disease can range from mild to life-threatening. Lupus primarily affects women of childbearing age, at a ratio of nine women to each man. In the United States, lupus is three times more common in black women than in white women.

The mice used for this research, a mutant strain known as MRL -lpr/lpr , "develop many features of human lupus, including kidney, joint, and lung disease," says Mountz. "They also develop autoantibodies characteristic of human lupus," he says. In addition, these mice develop lymphoproliferative (lpr) disease, that is, they produce abnormally high numbers of lymphocytes. MRL -lpr/lpr mice have a defect in the Fas ( lpr ) gene that leads to drastically reduced production of the Fas apoptosis protein. The Fas protein, located on cell surfaces, receives the orders that tell a cell to self-destruct. Activation of Fas sets off a program of events within the cell that lead to that cell's death.

Mountz, Dr. Jianguo Wu, and their colleagues at the University of Alabama and the Uniformed Services University of the Health Sciences in Bethesda, Maryland, showed that when the defective fas gene is replaced with a normal Fas gene, the mice no longer develop signs of disease. The researchers genetically engineered the mice to correct the defect in Fas production in white blood cells called T cells. In these Fas transgenic mice, the lymphoproliferative disease and kidney disease seen in the MRL -lpr/lpr mutant mice was eliminated, and autoantibody levels were reduced.

Preliminary research suggests that defects in apoptosis may also occur in people with lupus. Mountz and his colleagues are pursuing their research on lupus in both humans and mice. "The studies in mice and humans go hand in hand," says Mountz. "It is easy to test treatments in mice. We found one way to cure the mice; our goal is to find ways to cure the mice that would be applicable to humans, leading to safe and novel human therapies" he says.

The National Institute of Arthritis and Musculoskeletal and Skin Diseases leads and coordinates the Federal biomedical research effort in lupus by conducting and supporting research projects, research training, clinical trials, and epidemiologic studies, and by disseminating information on research results.

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Reference: Jianguo Wu, Tong Zhou, Jinju Zhang, Jin He, William C. Gause, and John D. Mountz. Correction of accelerated autoimmune disease by early replacement of the mutated lpr gene with the normal Fas apoptosis gene in the T cells of transgenic MRL -lpr/lpr mice. Proceedings of the National Academy of Sciences , March 15, 1994.