Dr. Taylor (right) and lab manager Kyle Gromer (left)
Immune Mechanisms of Pediatric Liver Disease
The Taylor Lab is committed to defining the immune mechanism of neonatal liver disease. Currently, the Taylor Lab’s primary focus is on the role for macrophages in cholestatic liver disease, particularly biliary atresia (BA), a neonatal cholestatic liver disease that is the leading cause of pediatric liver transplantation. BA is thought to arise from an aberrant immune response against a self-protein, leading to destruction of the extra-hepatic bile duct. While much prior work has focused on adaptive immunity in BA, growing evidence supports a role for innate immunity, and particularly macrophages, in the immune mechanism of disease. We are thereby using a combination of murine models and human samples to understand the precise role of macrophage subsets in BA with the ultimate goal to identify novel therapeutic targets.
In addition, clinical and translational work with Dr. Peter Whitington, now retired, has focused on gestational alloimmune liver disease (GALD), a materno-fetal alloimmune disorder that is a leading cause of neonatal acute liver failure. This work has led to advancements in knowledge of outcomes for infants with GALD and efficacy of preventative gestational treatment with intravenous immunoglobulin in future pregnancies. Dr. Taylor and Sue Kelly RN continue to collaborate with physicians nationally and internationally to provide care to affected newborns as well as mothers receiving intravenous immunoglobulin to prevent repeat occurrence after an index case. Ongoing and future translational research aims to find the liver antigen that is the target of antibody-driven immune injury and establish a serologic test that would aid in early diagnosis.
Current Research Projects
Macrophage Regulation of Immune Pathogenesis of Biliary Atresia
Biliary atresia (BA) is a cholestatic liver disease of infancy that is the leading cause of pediatric liver transplantation. BA is thought to arise from an aberrant immune response to an environmental trigger, however, the exact mechanism of disease progression remains unknown. Evidence points to a central role for macrophages in BA pathogenesis, however, macrophages are a heterogeneous and plastic cell population, and prior studies have not distinguished between subsets. We have demonstrated macrophage heterogeneity in pediatric cholestatic liver disease through single-cell RNA sequencing and are using this data to further define the disease mechanism.
To understand the precise role of these macrophage subsets we are performing functional studies utilizing the well-established murine model of BA as well as comparison to non-immune murine models of biliary obstruction. Additional human studies at diagnosis and the time of transplantation will further define the role of specific macrophage populations in disease onset and disease progression. Overall, we hope to identify new therapeutic targets for macrophage immune modulation in BA to prolong transplant-free survival.
Immune Modulation of Macrophages in Obstructive Cholestasis
Obstructive cholestatic liver diseases carry a high medical burden as there is no medical therapy to prevent disease progression and thus they remain a leading indication for liver transplantation. While the initial target in obstructive cholangiopathies is the bile duct, the immune response is a major cause for ongoing liver injury. Macrophages are known to play a significant role in the mechanism of cholestatic liver injury, however, disease-modulating immunotherapies have not been established and represent an unmet medical need. We have identified a unique population of macrophages expressing a gene previously shown to promote anti-inflammatory macrophage polarization. Using an innovative murine model of bile duct obstruction with reversal, we aim to stimulate this macrophage subset to promote conversion of pro-inflammatory macrophages into a critical pro-restorative subset. Data from this study may improve treatment strategies for cholestasis through macrophage immune modulation.
Clinical Outcomes in Neonatal Acute Liver Failure
To further the clinical knowledge of gestational alloimmune liver disease as well as other etiologies of neonatal acute liver failure, our team continues to pursue clinical and translational studies in this area. Ongoing single center and multi-center studies aim to better characterize the clinical features and outcomes for different etiologies of neonatal acute liver failure. Dr. Taylor and her team continues to collaborate with families affected by gestational alloimmune liver disease as well as treating physicians both nationally and internationally.
Sarah A. Taylor, MD - Principal Investigator Kyle D. Gromer – Research Associate Susan Kelly, RN – Research Coordinator Swati Antala, MD – Research Fellow
Lab phone number: 312.503.2191
Taylor SA, Yeap XY, Wang JJ, Gromer KD, Kriegermeier A, Green RM, Zhang ZJ. A novel murine model of reversible bile duct obstruction demonstrates rapid improvement of cholestatic liver injury. Physiol Rep 2020;8:e14446.
Taylor SA, Venkat V, Arnon R, Gopalareddy VV, Rosenthal P, Erinjeri J, Anand R, Daniel JF, Society of Pediatric Liver T. Improved Outcomes for Liver Transplantation in Patients with Biliary Atresia Since Pediatric End-Stage Liver Disease Implementation: Analysis of the Society of Pediatric Liver Transplantation Registry. J Pediatr 2020.
Taylor SA, Malladi P, Pan X, Wechsler JB, Hulse KE, Perlman H, Whitington PF. Oligoclonal immunoglobulin repertoire in biliary remnants of biliary atresia. Sci Rep 2019;9:4508.
Taylor SA, Kelly S, Alonso EM, Whitington PF. The Effects of Gestational Alloimmune Liver Disease on Fetal and Infant Morbidity and Mortality. J Pediatr 2018;196:123-128 e1.