Targeting and imaging of inflammatory circuits in CLAD

PROJECT SUMMARY / ABSTRACT Lung recipients suffer from shorter life spans and higher rejection rates when compared to other solid organ recipients. A major impediment to long-term lung transplant survival is chronic allograft dysfunction (CLAD). This fibrotic disease causes the progressive loss of pulmonary function for which there is no effective medical treatment. Based on outcomes studies that show club cell dysfunction and injury are linked to CLAD, we have developed a new mouse orthotopic lung transplant model that develops CLAD by recapitulating this clinically observed relationship. Using this innovative model, we have recently reported that classical monocyte (CM) differentiation into monocyte-derived alveolar macrophages results in the activation of tissue-resident memory CD8+ T cell activation (CD8+Trm) to injure bronchial epithelium and promote CLAD. We have also shown that we can image CLAD development using CCR2 molecular probe-based positron emission tomography (PET) imaging. Although CM and CD8+Trm activation is required for CLAD development, the pathways that regulate their local activation remain poorly described. New data from our lab show CM utilize different metabolic programs to facilitate graft infiltration and promote fate determination. We have also developed nanoparticle formulations to deliver metabolic inhibitors specifically to CM during CLAD pathogenesis. Finally, by identifying a novel receptor for club cell secretory protein (CCSP), we have generated pilot data that indicates club cells directly regulate CD8+Trm activation. Based on this new evidence, we propose to test whether (Aim 1) targeting metabolic adaption of CM and (Aim 2) recombinant human CCSP replacement therapy prevents CLAD through inhibiting CD8+Tm activation. Finally, in Aim 3, we propose to examine whether CCR2 molecular probe-based PET imaging can detect CLAD in human lung recipients. The overall goal of this project is to provide the basis to develop new CLAD prevention and detection strategies by uncovering immunological mechanisms that mediate CLAD pathogenesis.