BOSTON-April 22, 1998--Researchers at Harvard Medical School and the Center for Blood Research have identified a peptide that may serve as a template for a drug that can suppress the immune response with fewer side effects than immunosuppressants currently available. In addition to benefiting people who receive organ transplants, a drug based on this agent potentially could be used to treat chronic conditions caused by excessive or inappropriate immune responses, such as asthma, inflammation, allergies, and rheumatoid arthritis. Their findings are published in the April 24 Molecular Cell.
The two main immunosuppressant drugs used today, cyclosporin A and FK506, prevent the rejection of foreign organs or bone marrow by disrupting the signaling pathway that activates T cells. But both drugs can cause kidney and nervous system damage, making them unsuitable for wider clinical application. The newly identified peptide prevents a single, specific step in the immune system's signaling pathway, so researchers anticipate that it will not cause serious side effects.
Anjana Rao, professor of pathology, Patrick Hogan, investigator, and their colleagues at Harvard Medical School and the Center for Blood Research made a peptide that binds to calcineurin, a key molecule in the pathway that transmits signals from the T cell receptor to the nucleus. The key difference between how the peptide and the drugs cyclosporin A and FK506 work is the region on calcineurin where each of these agents bind. Cyclosporin A and FK506 block the active site of calcineurin and prevent it from acting on any other molecules within the cell. The peptide, on the other hand, only blocks specific binding between calcineurin and NFAT (nuclear factor of activated T cells). Other calcineurin functions are unimpeded.
With the peptide in place, calcineurin is unable to bind to the transcription factor NFAT and the signaling pathway is halted. In the absence of the peptide, NFAT moves into the nucleus and turns on expression of soluble immune factors such as the cytokine interleukin 2. Release of interleukin 2 activates neighboring T cells and escalates the immune response.
The pivotal role of NFAT in T cell activation and immunosuppression makes it an active area of current research. Two groups of Harvard investigators reported the structure of NFAT bound to DNA in the March 5 Nature and the March 6 Cell. Using x-ray crystallography and nuclear magnetic resonance respectively, the scientists were able to see how NFAT attaches to DNA, and how its structure changes during this process. Knowing what NFAT looks like improves researchers' ability to design new drugs to interfere with its activity and suppress the immune system.
The above story is based on materials provided by Harvard Medical School. Note: Materials may be edited for content and length.
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