In spite of powerful immunosuppressive drugs approximately 20% of kidney grafts fail during the first year. Virtually 100% of patients who receive a kidney or liver transplant will at some time be treated for an opportunistic infection and a major problem in liver transplantation is the development of recurrent viral hepatitis in the transplanted organ. The interferons, interferon-gamma (IFN-gamma), interferon-alpha (IFN- alpha) and interferon-Beta (IFN-beta) are secreted polypeptides that mediate pleiotropic functions in a wide variety of cell types through multi-component cell surface receptors. While they are recognized to activate components of the immune system, interferons also have important antifibrogenic, antibacterial and antiviral effects which can enhance graft and patient survival. More is known about the structure and function of the IFN-gamma receptor than the IFN-alpha receptor or the IFN-beta receptor although IFN-alpha and IFN-beta are widely used in the treatment of human diseases. The IFN-gamma receptor complex is composed of two chains, a ligand-binding molecule that binds IFN-gamma with high affinity in a species-specific manner and a signaling molecule that interacts with the receptor and cytoplasmic signal transduction pathways. Only a ligand binding component of the IFN-alpha receptor complex has so far been isolated and the receptor complex for IFN-beta remains uncharacterized. Chromosome transfer experiments suggest that the ligand-binding and signaling molecules of the IFN-alpha and the IFN-beta receptor(s) are encoded by gene(s) on human chromosome 21. We propose to characterize the ligand-binding domain of the IFN-gamma receptor in order to identify the regions involved in ligand binding and in the interaction with the signaling molecule. We will apply these finding to an analysis of the larger and more complex IFN-alpha receptor. We propose to isolate the human chromosome 21-specific IFN-alpha and IFN- beta receptor molecules and will examine the structure and function of the cytoplasmic domain of the IFN-alpha receptor to understand how the receptor mediates IFN-alpha signal transduction. Little is known about how the interferons interact with the multiple components of the receptors or how the receptor components interact with each other. The information generated from these studies may provide a rational basis for the development of agonists and antagonists which may be clinically useful in preventing acute graft rejection and chronic graft failure.
| Spencer, S D; Di Marco, F; Hooley, J et al. (1998) The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med 187:571-8 |
