Cytokine Receptors, Drug Resistance, Oxidative Stress and Cell Death

Over the years my lab studied the mode of action of various cytokines, focusing on the identification of cytokine receptors and binding proteins. We Isolated and characterized the human interferon alpha, demonstrating that it consists of multiple species encoded by several genes. Together with Dr. Daniela Novick and others, we cloned the ligand-binding subunit of the Type I interferon receptor (IFNAR2) and IL-18 binding protein, a unique cytokine inhibitor. We have isolated and identified many soluble receptors, including those of IL-6, IFN-gamma, TNF, and LDL. In later years we discovered that the LDL receptor and its other family members are the entry ports of vesicular stomatitis virus and VSV-G-pseudotyped lentiviral vectors, an observation highly relevant to gene therapy and oncolytic virotherapy. In parallel, we studied the role of C/EBPβ in cell survival and death, with a particular emphasis on tumor drug resistance. We also discovered that chemotherapy and endoplasmic reticulum stress induced the production of leukotrienes in non-immune cells and these, in turn, have been the key inducers of reactive oxygen species, oxidative DNA damage, and subsequent cell death. More recently, we are focusing on gene therapy and oncolytic virotherapy, aiming to achieve cell and tissue specificity. So far, our studies led to the development of three approved biological drugs (Roferon A, REBIF, Enbrel) and a fourth one, based on IL-18BP is currently in advanced clinical trials.