Immunosuppressive treatment is necessary to prevent rejection of an organ after transplant and has great potential for treating chronic inflammatory diseases.
However, currently available immunosuppressant drugs can pose serious health risks, restricting their long-term use. Now, new research findings may lead to the development of immunosuppressant drugs that have fewer adverse side effects. The study, published by Cell Press in the March 13th issue of the journal Molecular Cell, reveals detailed information about how drugs commonly used to prevent transplant rejection interact with their target.
Calcineurin (CN) is a highly conserved protein that plays a multitude of roles in diverse biological processes. Previous work has shown that CN regulates a protein called nuclear factor of activated T cells (NFAT) in mammals and that this regulation involves a docking interaction between CN and NFAT. The CN-NFAT pathway is known to play a critical role in processes such as inflammation, diabetes and cardiac hypertrophy.
CN is the target of the immunosuppressant drugs cyclosporine A (CsA) and FK506 which are used to prevent rejection after a transplant. These drugs have also been used to treat atopic dermatitis, severe asthma, and refractory rheumatoid arthritis. "CsA and FK506 each form complexes with a specific immunophilin binding proteins and it is these complexes, called IS-IP complexes, that inhibit CN activity," says senior study author Dr. Juan Miguel Redondo from the Department of Vascular Biology and Inflammation at the Centro Nacional de Investigaciones Cardiovasculares in Madrid.