Investigators at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Pfizer Global Research and Development and Stanford University have collaborated in studying a new immunosuppressant drug, CP-690,550, that may avoid some of the common side effects associated with other medications that curb the immune system. The new drug, discovered by Pfizer researchers, may be of major importance for those who are treated with immunosuppressants for organ transplants or autoimmune diseases.
John O'Shea, M.D., Yong-Jie Zhou, M.D., and their team in the NIAMS Molecular Immunology and Inflammation Branch joined scientists from Pfizer and Stanford in developing and studying the drug. CP-690,550 was tested in mice with heart transplants and in monkeys with kidney transplants done by Stanford. In both cases, animals treated with CP-690,550 survived much longer than untreated animals. None of the treated animals showed signs of such immunosuppressant side effects as increased cholesterol, blood sugar, blood pressure or increased white blood cell count. The animals also showed no significant decreases in white blood cells or platelets.
The new drug, reported in the journal Science, inhibits the enzyme Jak3, a protein discovered by the NIAMS team in 1994 that is found only in immune system cells. The new study shows that inhibiting this enzyme has the effect of suppressing the immune system, while not affecting other systems of the body. Current immunosuppressant drugs target enzymes found in cells throughout the body, resulting in the toxic side effects. The Jak3 inhibitor has the advantage of selectively targeting a protein that only has effects on immune cells.
The finding culminates a long process of research and discovery by the NIAMS team. After discovering Jak3, the team demonstrated that this protein, called a kinase, was critical for the cell signaling process resulting in the development of infection-fighting white blood cells. They went on to show that the mutation of the gene encoding Jak3 was responsible for a form of severe combined immunodeficiency (SCID). Because Jak3 is essential for immune cell function, and because its expression is limited to blood cells, the team proposed that inhibiting Jak3 might be the basis for a new class of immunosuppressant drugs. The group then entered into a collaborative research and development agreement with Pfizer -- a partnership that has enabled Pfizer to develop this new drug.
CP-690,550 is the first Jak3 inhibitor to show positive results in primates. Further animal studies are being conducted to determine if this drug could be used successfully and safely in humans.
Immunosuppressant drugs, which inhibit the body's immune response, are given to prevent the body from rejecting transplanted organs, and are also used to treat autoimmune diseases such as lupus, rheumatoid arthritis, eczema and psoriasis. Autoimmune diseases cause the immune system to attack healthy, normal tissue as if it were a foreign substance. The finding that CP-690,550 selectively suppresses the immune response in transplant rejection with minimal toxicity also suggests that a Jak3 inhibitor might be useful in the treatment of autoimmune diseases.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. 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. Changelian P, et al. Prevention of organ allograft rejection by a specific Janus Kinase 3 inhibitor. Science, 2003;302:875-878.
The above story is based on materials provided by NIH/National Institute Of Arthritis And Musculoskeletal And Skin Diseases. Note: Materials may be edited for content and length.
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