B Cell-Fibroblast Crosstalk Promotes Chronic GVHD of the Lung

ABSTRACT This K38 award is designed to support Dr. Sonali Bracken’s research training and accelerate her path to an independent research career in the field of autoimmunity. Dr. Bracken is a clinical rheumatologist at Duke University with a Ph.D. in Immunology. Her long-term goal is to improve the health and longevity of patients

with autoimmune, fibroproliferative disorders through the development of B cell-targeted therapies. Through this award, Dr. Bracken will develop expertise in the mechanisms of fibrosis, expand her proficiency in fundamental immunological laboratory techniques, and build foundational skills in data analysis and laboratory

management. Her research progress and career development will be overseen by a multidisciplinary mentorship team headed by both Dr. Stefanie Sarantopoulos, an expert in bone marrow transplant and B cell signaling, and Dr. Scott Palmer, an expert in the field of lung fibrosis and transplantation. Dr. Bracken will also

benefit from a wealth of resources available through Duke University that are aimed at training physician scientist leaders. The objective of this application is to delineate immune pathways that contribute to lung fibrosis in patients with chronic graft-versus-host disease (cGVHD). cGVHD is a leading cause of morbidity and

mortality after allogeneic hematopoietic stem cell transplantation that results from multiorgan inflammation and fibrosis. In up to twenty percent of patients with cGVHD, fibrosis impacts the lungs and can cause respiratory failure. B cells are known contributors to the pathogenesis of cGVHD. The central hypothesis of this application

is that B cells and fibroblasts undergo crosstalk that leads to bidirectional cellular activation and ultimately promotes lung fibrosis. This hypothesis will be investigated via two aims, the first of which will examine the mechanisms by which hyperactive Toll Like Receptor 7 signaling in B cells drives fibroblast activation in the

lung. This will be accomplished through 1) co-culture assays using cGVHD patient B cells and primary human lung fibroblasts 2) immunofluorescence microscopy in explanted cGVHD patient lung tissue samples and 3) use of a well-characterized cGVHD mouse model that permits selective deletion of Toll Like Receptor 7

signaling pathway components in donor B cells. The second aim will examine the role of the fibroblast extracellular matrix component hyaluronan in activating cGVHD B cells from the lung through the CD44 receptor using in vitro stimulation assays. It will also examine the differential effects of high- and low-molecular

weight hyaluronan on lung cGVHD severity using a mouse model. Altogether, these experiments are expected to provide important insights about the role of B cells in promoting fibrosis in lung cGVHD. Ultimately, this knowledge can be utilized to therapeutically target specific points of B cell-fibroblast crosstalk that are critical

for promoting fibrosis in cGVHD. It is likely that the knowledge gained from this proposal will also be relevant to mechanisms that drive lung fibrosis in autoimmune connective tissue disease. Furthermore, this proposal will position the candidate to submit a K08 Career Development Award during the final year of the award period.