Robert Wood Johnson Medical School
Department of Pharmacology
Research Tower, Rm 729
Piscataway, NJ 08854
Structure and function of interferons and interferon receptors; development of Type I IFN antagonists; role of IFNs in autoimmune diseases such as lupus
We are currently interested in 2 related areas: (1) understanding the differential action of the 17 human Type I interferons (IFNs); (2) the role of IFNs in systemic lupus erythematosus ("lupus") and autoimmunity, including the development of IFN analogues that act as competitive antagonists to endogenous IFNs.
The 13 IFN-alphas, and IFN-beta, IFN-omega, IFN-kappa and IFN-epsilon produce differential activation of cells and, in some cases, different physiological and clinical efficacies. However, they all act through a common heterodimeric cell-surface receptor, IFNAR. Recent evidence suggests that, to a first approximation, some of the differential effects come from different interactions of the IFNs with the low-affinity receptor subunit IFNAR-1. Dr. Langer's group previously identified regions of IFNAR-1 that are involved in binding IFNs. More recently, his group has used mutagenesis to help identify critical regions of Type I IFNs that interact with IFNAR-1. Continued mutagenesis and structure/function studies will help us understand the degree to which these interactions modulate IFN responses.
Our work on understanding the IFN/IFNAR-1 interaction is critical to our efforts to develop novel competitive antagonists for Type I IFNs. There is good evidence that the aberrant production of Type I interferons in people with lupus helps drive the progression of this disease. Type I IFNs may also be involved in the pathogenesis of several other autoimmune diseases, and in other clinical situations. Dr. Langer’s group is trying to genetically engineer and produce Type I interferon variants that can block the receptor binding and activity of endogenous Type I interferons, i.e., they will act as competitive antagonists. Antagonists are being designed and tested both for use in humans and for animal models.