Rene S. Bermea

Current guidelines define progressive pulmonary fibrosis (PPF) as the presence of at least two of the following three changes within 12 months: worsening symptoms, lung function decline, or new/extending radiographic abnormalities [1, 2]. However, limiting assessment to subsequent progression may miss high-risk patients: those presenting with severely impaired lung function may meet none of the criteria if later tests remain unchanged, delaying therapy initiation and close monitoring. Therefore, we examined whether baseline forced vital capacity (FVC) was associated with an increased risk of lung transplantation or death in non-idiopathic pulmonary fibrosis (non-IPF) interstitial lung disease (ILD) patients whose FVC declined by <5 percentage points predicted during the first year after diagnosis.

Tissue-specific T cell immune responses play a critical role in maintaining organ health but can also drive immune pathology during both autoimmunity and alloimmunity. The mechanisms controlling intratissue T cell programming remain unclear. Here, we leveraged a nonhuman primate model of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation to probe the biological underpinnings of tissue-specific alloimmune disease using a comprehensive systems immunology approach including multiparameter flow cytometry, population-based transcriptional profiling, and multiplexed single-cell RNA sequencing and TCR sequencing. Transcriptional profiling revealed substantial biological differences between T cells infiltrating the lung and liver during aGVHD. These included enrichment for transcriptional pathways controlling extracellular matrix remodeling and chemotaxis in the lung and enrichment for transcriptional pathways linked to nucleic acid metabolism and proliferation in the liver. Single-cell RNA sequencing and TCR sequencing substantiated divergent organ-specific transcriptional programing of tissue-infiltrating T cells, which was linked to clonal expansion, with expanded clones progressively enriched for C-X3-C motif chemokine receptor 1 ( CX3CR1 )–expressing CD8 effector T cells in the lung and eomesodermin ( EOMES )–expressing CD8 effector-memory T cells in the liver. This divergent evolution of T cells was maintained even for T cells sharing the same TCRs, indicating its independence from antigen specificity. Together, these results provide insights into the role that tissue microenvironment–derived signals play in local T cell transcriptional programming during alloimmune-mediated clonal expansion and suggest potential opportunities to develop tissue-specific therapeutics to curtail pathogenic immunity after transplant.

Background. There are known racial disparities in the organ transplant allocation system in the United States. However, prior work has yet to establish if transplant center decisions on offer acceptance—the final step in the allocation process— contribute to these disparities. Objective To estimate racial differences in the acceptance of organ offers by transplant center physicians on behalf of their patients. Design Retrospective cohort analysis using data from the Scientific Registry of Transplant Recipients (SRTR) on patients who received an offer for a heart, liver, or lung transplant between January 1, 2010 and December 31, 2020. Setting Nationwide, waitlist-based. Patients 32,268 heart transplant candidates, 102,823 liver candidates, and 25,780 lung candidates, all aged 18 or older. Measurements 1) Association between offer acceptance and two race-based variables: candidate race and donor-candidate race match; 2) association between offer rejection and time to patient mortality. Results Black race was associated with significantly lower odds of offer acceptance for livers (OR=0.93, CI: 0.88-0.98) and lungs (OR=0.80, CI: 0.73-0.87). Donor-candidate race match was associated with significantly higher odds of offer acceptance for hearts (OR=1.11, CI: 1.06-1.16), livers (OR=1.10, CI: 1.06-1.13), and lungs (OR=1.13, CI: 1.07-1.19). Rejecting an offer was associated with lower survival times for all three organs (heart hazard ratio=1.16, CI: 1.09-1.23; liver HR=1.74, CI: 1.66-1.82; lung HR=1.21, CI: 1.15-1.28). Limitations Our study analyzed the observational SRTR dataset, which has known limitations. Conclusion Offer acceptance decisions are associated with inequity in the organ allocation system. Our findings demonstrate the additional barriers that Black patients face in accessing organ transplants and demonstrate the need for standardized practice, continuous distribution policies, and better organ procurement.