Genome Transplant Dynamics

Acute rejection (AR) occurs within the first 6 months after transplantation in 20 percent of heart- transplant patients and in 50 percent of lung-transplant patients. Given the often silent clinical presentation of AR, these patients require monitoring with repeated invasive and costly endomyocardial (EMB) or transbronchial biopsies (TBBx). Since organ transplantation is essentially genomic transplantation, our prior studies leveraged the use of distinctive graft and recipient genotype single-nuclear polymorphisms (SNPs) to barcode donor DNA circulating in recipient serum. We have shown that levels of donor DNA measured as the percentage of circulating donor-derived cell-free DNA (cfDNA) correlate with AR diagnosis and severity as detected by biopsy. The performance receiver operator curve (ROC) of cfDNA yielded an area under the curve (AUC) of 0.83. Using this technique, we can diagnose AR by measuring elevations in cfDNA up to 5 months before EMB-detected pathology. While these findings suggest that monitoring cfDNA may offer a high-performing, non-invasive, and early diagnostic tool of AR, further validation studies are required to determine its clinical utility. The ability to diagnose AR earlier than is possible with a biopsy offers an opportunity to investigate the pathogenesis of rejection as well as to identify potential AR biomarkers. Thus, the primary objective of this study is to validate the predictive accuracy and ROC characteristics of cfDNA for AR in a multicenter, prospective cohort study of heart and lung transplant patients, recruited through a consortium of transplant centers. The secondary objective is to determine the association between early graft injury caused by acute rejection and infection and the development of chronic rejection, i.e., chronic lung allograft dysfunction (CLAD) or chronic allograft vasculopathy (CAV). The exploratory objectives are: 1) to compare cfDNA characteristics in AMR (antibody-mediated rejection) and ACR (acute cellular rejection), 2) to study early immunological changes associated with a significant rise in cfDNA, and 3) to examine changes in microbiome architecture and other cell-free nucleic acids in rejection, 4) to determine if cfDNA trends correlate with treatment response for transplant complications, 5) to determine if the level of pre-transplant cfDNA identify patients at high risk of rejection post-transplant, 6) to determine genetic variants associated with post-transplant risk of rejection, high cfDNA levels and other complications.