Summary Up to 80% of lung transplant recipients who survive beyond five years will develop chronic lung allograft dysfunction (CLAD), a heterogenous, progressive condition characterized by the gradual and irreversible functional decline eventually leading to death. Once developed, the majority of CLAD types do not respond well to currently available therapeutic interventions. Early diagnosis of suspected CLAD is therefore crucial to efforts aimed at the delaying disease onset and/or progression, which usually proceed via the aggressive treatment of associated immunological risk factors. Despite recently revised criteria, the current clinical reliance on spirometry to diagnose suspected CLAD suffers from several disadvantages: namely, the global nature of the measurements provided by pulmonary function tests (PFTs), their failure to differentiate between rejection and infection as the cause of functional decline, frequent inter-observer disagreement in interpreting their results and, finally, their inability to improve the targeting of transbronchial biopsy. An imaging modality capable of sensitively and accurately detecting CLAD-onset earlier and with more spatial specificity would provide significant clinical value. In response to this need, the proposed project will use the sensitive, regional measurements of lung function which various hyperpolarized xenon-129 MRI techniques are uniquely capable of providing to develop a set of imaging markers capable of diagnosing suspected CLAD before spirometric measurements reveal a clinically significant functional decline; ideally, these markers will also enable a distinction to be made between obstructive and restrictive forms of CLAD before either becomes symptomatic. The first task of this project will be to use multi-breath HP xenon-129 MR imaging to establish regional specific ventilation (SV) and alveolar oxygen tension (PAO2) as imaging markers for the early diagnosis of obstructive CLAD: increased heterogeneity in these sensitive measures of gas replacement dynamics within the transplanted lung will offer an earlier indication of CLAD-associated functional decline than spirometry. Next, we will use dissolved-phase HP xenon-129 imaging to quantify the efficiency of alveolar gas exchange and transport in order to detect the fibrotic and bloodflow impediments to pulmonary function associated with restrictive CLAD. Finally, we will attempt to radiologically define several novel sub-classifications of CLAD related to known associated risk factors such as ischemia reperfusion injury, respiratory infection, antibody- mediated injury and gastroesophageal reflux.