Cytomegalovirus Immune Responses in Chronic Lung Allograft Dysfunction Pathogenesis

While veterans are at increased risk for end-stage lung diseases necessitating lung transplantation, survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), a syndrome of declining lung function post-transplant. Cytomegalovirus (CMV) is common in the US population and a major risk factor for CLAD and death following lung transplantation. Clinically available CMV immune response assays have limited utility in predicting CMV reactivation risk, and despite recently available new therapies, we lack an understanding of how to manage CMV to prevent CLAD. While immune responses to CMV are heterogenous, emerging technologies now make it possible to separate protective and maladaptive CMV-specific immune responses. Preliminary data in this proposal distinguish such CMV-associated immune response patterns with differential associations with CLAD, including graft NKG2C+ NK cells that potentiate CLAD risk and CD57+ KLRG1+ TEMRA, a subset of highly differentiated CD8+ T cells, that are associated with improved outcomes. We also identified novel CMV- associated bronchoalveolar lavage (BAL) macrophage subsets and peripheral blood epigenetic signatures that capture previously uninvestigated CMV-specific immune subsets. Building on these novel tools, this proposal tests the overall hypothesis that CMV-specific immune responses differentially impact CLAD risk across the life of the allograft. Aim 1 examines whether primary graft dysfunction (PGD) potentiates maladaptive CMV-specific immune responses. In a prospectively enrolled cohort, we well quantify our novel CMV-specific subsets in peripheral blood and BAL fluid to determine how early graft complications shape the interactions between CMV and graft rejection. Aim 2 will assess CMV-specific immune response subtypes in the airway at the time of CLAD onset. Using already collected airway brush samples, we will quantify CMV-specific immune phenotypes in the airways at time of allograft damage to dissect protective and maladaptive responses. Finally, in Aim 3, we will use previously collected explant tissue taken at the time of re-transplantation for CLAD to determine which CLAD pathologies co-localize with CMV-specific immune responses and how CMV may drive parenchymal cell compositional changes. Together, these aims will provide a comprehensive understanding of CMV-specific immune responses across the life of the allograft. These aims will leverage novel techniques in epigenetic, single cell, and spatial transcriptional profiling using bronchoalveolar lavage, airway brushing, and explant tissue. The feasibility of these aims is supported by established workflows for prospective recipient enrollment in Aim 1 and already collected biorepository samples for Aims 2 & 3, with demonstrated expertise in the proposed approaches. Differentiation of protective and maladaptive CMV-specific immune responses is a critical step in refining CMV prophylaxis and management to improve lung transplant outcomes and would drive a paradigmatic shift in clinical management. Broad implications of these findings may extend to acute respiratory distress syndrome, fibrotic and inflammatory interstitial lung diseases, and constrictive bronchiolitis, which all share pathologic features with lung transplant rejection pathology, while insights into CMV management extend to HIV, and other transplant settings where CMV impacts veteran health. Project Number: 2I01CX002011-05A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: JOHN GREENLAND | Institution: VETERANS AFFAIRS MED CTR SAN FRANCISCO, SAN FRANCISCO, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 PULM-T (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11047643