The microbiome-induced immune response role in bronchiolitis obliterans syndrome following allogeneic hematopoietic cell transplantation
Adi Nagler
PhDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2026
The microbiome is increasingly recognized as contributing to chronic graft-versus-host disease (cGVHD). I hypothesize that microbial antigens drive the devastating complication of bronchiolitis obliterans syndrome (BOS). To determine if such antigen targets are at the heart of BOS pathology, I will integrate spatial transcriptomic approaches, immunopeptidome analysis, and direct antigen specificity testing of TCRs from biospecimens collected from preclinical models and patient biospecimens.
Chronic graft-versus-host disease (cGVHD) is a challenging complication of bone marrow transplant, which is a potentially curative therapy for blood cancers. A subtype of cGVHD that is typically fatal is Bronchiolitis Obliterans Syndrome (BOS), and it develops from an immunologic attack of the lung tissue. The treatment options for BOS are currently extremely limited. Therefore, an in-depth investigation into the understanding of how BOS develops is of high priority in order to develop better strategies to prevent or treat this devastating complication. Although T cells are thought to play a central role in starting the development of BOS, it remains unknown which peptides that are expressed on the surface of lung tissues, called ‘antigens’, are recognized by those T cells that are involved in this disease process. Growing evidence suggests that alterations in the composition of colonizing bacteria in the lung and/or gut (the so-called ‘microbiome’) may play a role in this disease, but exactly which types of bacteria are involved in this process, which peptide antigens, and to what extent do these antigens control the composition of BOS-associated T cells and their localization in lung tissue is entirely unknown. I will develop a new strategy to detect the bacteria and the pattern of T cells in affected lung tissue, determine whether or not these T cells are reactive to colonizing bacteria, and test if indeed these microbiome-derived antigens stimulate immune responses in those T cells that we visualize as present and expanded in diseased lung tissue. This will be performed in both an established and informative mouse model of BOS and from human tissue samples at the initiation or progression stages of cGVHD. My hope is that this study will not only fundamentally change our understanding of BOS, but also provide us with the insights to generate more effective approaches to target this devastating disease.