Role of plasma cells in chronic rejection after lung transplantation - SUMMARY Lung transplantation (LTx) is the only life-saving intervention for many patients with end-stage lung disease. The long-term survival after LTx, however, is severely limited primarily due to chronic rejection of the allograft (chronic lung allograft dysfunction - CLAD). Bronchiolitis obliterans syndrome (BOS) is the most frequent phenotype of CLAD. It is characterized by partial to complete obliteration and luminal occlusion of distal airways and includes features of subepithelial cellular inflammation, peribronchial and interstitial fibrosis, and selective loss of club cells within the airway epithelium. The pathogenesis of CLAD remains poorly understood, largely due to a lack of clinically relevant animal models, but includes influx and activation of cell populations of the innate and acquired immune system, tissue remodelling, and distorted immune- epithelial cell crosstalk. However, which specific immune cell populations drive tissue remodelling in the transplanted lung remains unknown. We have recently discovered a significant increase in B cell populations and Marginal Zone B And B1 Cell Specific Protein (MZB) 1-positive plasma cells in rejected lungs, both in lungs from a novel mouse model of chronic rejection after orthotopic LTx, as well as in retransplanted CLAD patients. We showed that an innate-like B-1B population served as a progenitor pool of MZB1+ plasma cells and that B cell deficiency prevented chronic rejection in mice. Systemic depletion of B cells, however, is associated with increased risks of concomitant infections, in particular in patients routinely receiving high doses of immunosuppressive regimen, such as LTx patients, thus requiring more nuanced approaches to modify this pathogenic B and plasma cell populations. Therefore, the overarching goal of this application is to define the spatiotemporal profile and cellular heterogeneity of MZB1+ B and plasma cell populations over time after LTx and interrogate their mechanistic contribution to chronic rejection by manipulation their abundance and function in vivo. We hypothesize that plasma cells accumulate in chronically rejected lungs in peribronchial regions and cause increased peribronchial fibrosis and decreased lung function in chronic rejection. To test this hypothesis, we propose the following aims: Aim 1: To provide a comprehensive and detailed map of B and plasma cell gene expression profiles, population heterogeneity, and temporal dynamics in the chronically rejected lung after LTx. Aim 2: To mechanistically interrogate whether deletion of MZB1 or blocking the differentiation of MZB1+ plasma cells from B-1B cells prevents tissue fibrosis, lung function deterioration, and chronic rejection after orthotopic LTx in mice.
