GRAfT 2.0. A Multimodal Prospective Approach to Define the Mechanisms and Clinical Features of Acute and Chronic Rejection in Lung Transplantation

Study Description: Our hypothesis is that lung transplant recipients with donor-specific antibodies (DSA) who develop AMR (DSA+/AMR+) exhibit distinct molecular mechanisms compared to DSA+/AMR- and DSA-recipients. This study will recruit patients with progressive lung disease or who are being evaluated or have received a lung transplant to the NIH Clinical Center to investigate these differences. Participants will undergo blood draws, bronchoscopy with bronchoalveolar lavage, imaging and other diagnostic testing. After the initial visit, participants will continue routine care in their transplant programs with multiple planned NIH follow-up visits for blood draw and testing/sampling. The primary goal of this proposal is to profile the molecular changes from DSA detection to the development of acute rejection (AR) and subsequent development of chronic lung allograft dysfunction (CLAD). Secondary goals of the study are to profile changes in pulmonary function testing, pulmonary imaging, surveillance bronchoscopy, and advanced bronchoscopy measures that coincide with the molecular changes. The dynamic assessment is poised to identify actionable timing and molecular targets to preemptively treat patients before AMR develops and to halt progression to CLAD. Objectives: Primary Objective: -To identify molecular pathways associated with development of AMR from DSA Secondary Objectives: * To identify clinical subtypes (endotypes) of AMR * To identify molecular and clinical pathways associated with development of CLAD from AMR Endpoints: Primary Endpoint: -Multi-omic molecular differences between DSA+ participants who progress to AMR (DSA+/AMR+), DSA+ participants who do not progress to AMR (DSA+/AMR-), and DSA- participants. Secondary Endpoints: * Multi-omic molecular differences between participants who progress to CLAD (CLAD+), and no CLAD (CLAD-) * Physiological changes (PFT, 6MWT) between (DSA+/AMR+), (DSA+/AMR-), and DSA- groups. * Physiological changes (PFT, 6MWT): Between CLAD+, and CLAD- participants * Imaging findings differences (low dose CT, MRI, Confocal Microscopy) between (DSA+/AMR+), (DSA+/AMR-), and DSAgroups. * Imaging findings differences (CT, MRI, Confocal Microscopy): Between CLAD+, and CLAD- participants