Modeling Lupus Nephritis in a Human Kidney Microphysiological System
Abstract
The kidney is highly susceptible to injury from many systemic inflammatory and autoimmune diseases, including systemic lupus erythematosus (SLE), which is one of the Fiscal Year 2019 Lupus Research Program Topic Areas. Among people with SLE, kidney involvement (lupus nephritis) affects 60%-80% of SLE patients, and is recognized as a main contributor to morbidity and mortality. End stage renal disease occurs in ~25% of SLE patients within 15 years of onset, even with modern day immunosuppressive treatment. The incomplete understanding of SLE and lupus nephritis pathogenesis, and the lack of successful targeted therapeutic development constitutes a significant unmet need. Understanding how human immune system mediates kidney injury is critical for developing new safe and effective treatments for lupus nephritis. Clinical research has shown that the extent of injury to the blood vessels and tubules in the kidney cortex (called the tubulo-interstitium) is the most strongly correlated with the severity of lupus nephritis and is the best predictor in determining lupus nephritis outcomes. We have developed a three-dimensional flow directed “kidney-on-a-chip” populated with human kidney cells, with functional characterization of key component structures of the kidney cortical tubulo-interstitium. Use of this kidney-on–a-chip has been successful in developing robust in vitro models of multiple kidney diseases. Here we propose to use this system to test the hypothesis that the initiating mechanisms and response to kidney damage in SLE can be accurately identified for the first time. We will integrate immune cells, antibodies, and inflammatory factors into this system in order to model the role of vascular injury in initiating tubulo-interstitial disease in lupus nephritis and quantify tubulo-interstitial damage by study the immunologic, protein, and RNA transcription profiles as well as biomarkers of kidney injury. We will determine the function of cell types attracted to tubules following injury. To accomplish this goal, we have established a multidisciplinary investigative team with expertise in “organs on chips,” systemic lupus erythematosus, immunology, kidney physiology and pathology, stem cell biology, cellular and molecular biology, biomedical engineering, genomics, computational biology, and biostatistics, with the field-leading expertise needed to for modeling the complex pathways of immune system activation in lupus nephritis. Our overall goal is to use these pre-clinical studies to discover more effective strategies for treating and curing individual patients with SLE, so that clinical studies can then be conducted to improve their quality and quantity of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010666
Entities
People
- Jonathan Himmelfarb
Organizations
- United States Army
- University of Washington