Elucidating Effector CD8 T-Cell – Kupffer Cell InterferonGamma Interaction in Pediatric Activated T-cell Acute Liver Failure

PROJECT SUMMARY- Elucidating Effector CD8 T-Cell –Kupffer Cell- Interferon Gamma Interaction in Pediatric Activated T-cell Acute Liver Failure The overall goal of this five-year proposal for a Mentored Clinical Scientist Research Career Development Award is for me to become an independent academic investigator in the field of liver immunology. After graduating from Tel Aviv University School of Medicine, I completed my pediatric residency at Children's Hospital at Montefiore. I then pursued fellowship training in Pediatric Gastroenterology and Transplant Hepatology at Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). I joined the faculty of CHOP and Penn as an Attending Physician and Instructor in the Division of Gastroenterology. I continued my scientific training by completing a Masters in Translation Research at Penn 10/2024. During my fellowship, I developed a clinical and research interest in why dysregulated immune responses result in Pediatric Acute Liver Failure (PALF). My mentor for this award, Dr. Edward M. Behrens, is a physician-scientist with a longstanding track record of scientific innovation and providing exceptional training to mentees. As an internationally recognized expert in inflammatory disorders, Dr. Behrens's work complements my own, and we are poised for productivity. My scientific advisory committee includes scientists and physician-scientists with expertise in all aspects of the proposed work, from CD8 and macrophage biology to next-generation sequencing and spatial transcriptomics. Scientifically, this proposal focuses on the role of hepatic interferon-gamma (IFN-) response in the most common cause of PALF, termed Pediatric Activated T-cell Hepatitis/ALF (TC-PALF). TC-PALF is characterized by an elevated Th1 immune response with a hepatic IFN- transcriptional signature and an abundance of hepatic effector cytotoxic T lymphocytes (eCTL) expressing markers of tissue residence (CD8+, CD103+, perforin+) and macrophages. Under the guidance of Dr. Behrens, I previously discovered that hepatic parenchymal response to IFN- results in exacerbated liver injury in a mouse model of Hemophagocytic Lymphiohistiocytosis (HLH), a rare autoinflammatory disorder characterized by high circulating IFN- and PALF. However, how specific hepatic constituents respond to this cytokine in TC-PALF remains unknown. Based on prior literature and my preliminary data, my central hypothesis is that IFN- directly affects Kupffer Cell (KC) biology and drives liver injury in both murine and human TC-PALF, independent of its effect on intrahepatic and peripheral lymphocytes. The aims of this proposal are to establish: 1) the mechanism by which KCs respond transcriptionally and functionally to IFN- in a murine model of TC-PALF, and 2) the spatial relationship between IFN- responsive KCs, hepatocytes and eCTLs in both human and murine TC-PALF. This proposal will close major gaps in knowledge regarding the mechanism by which IFN- acts on hepatic parenchymal cells to develop hepatic-specific therapies and improve native-liver survival for patients. In accordance with my career development objective to become a field leader in liver immunology, my scientific proposal complements my current proficiency in cellular immunologic methods with training in advanced hepatocyte and macrophage biology and bioinformatic methods.