Researchers Identify Candidate Immunosuppressant With Fewer Side Effects

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 pa

Contact: Peta Gillyatt
Harvard Medical School

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