Researchers at HMS and the Center for Blood Research have now discovered a potential therapeutic replacement. In addition to preventing rejection, such a drug may provide treatment for asthma, inflammation, allergies, and other autoimmune diseases caused by excessive or inappropriate immune responses. The study is published in the April 24 Molecular Cell and was supported in part by the National Institutes of Health. Despite some evidence that traditional immunosuppressants could be useful in autoimmune and inflammatory diseases, the side effects are usually too severe for use in patients whose disease is not life-threatening, says Hogan. Although they don't yet have a compound ready for in vivo use, Hogan and Rao anticipate that a drug based on their peptide would avoid these side effects by disrupting only a single step in the activation pathway of T cells.
Traditional immunosuppressants cause widespread inhibition of the pathway.
Calcineurin binds to the transcription factor NFAT and activates it by removing phosphate groups. Once activated, NFAT moves into the nucleus and turns on expression of cytokines such as IL-2. With the inhibitory peptide in place, calcineurin is unable to bind to NFAT and the signaling pathway is blocked. By contrast, FK506 and cyclosporin A disrupt the pathway by blocking calcineurin's active site and preventing it from dephosphorylating all substrates. This broad inhibition may account for the toxic side effects associated with these immunosuppressants.