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 cell-free donor-derived DNA (%ccfdDNA) correlates with AR
diagnosis and severity as detected by biopsy. The performance receiver operator curve (ROC)
of %ccfdDNA yielded an area under the curve (AUC) of 0.83. Using this technique, we can
diagnose AR by measuring elevations in %ccfdDNA up to 5 months before EMB-detected pathology.
While these findings suggest that monitoring %ccfdDNA 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 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 %ccfdDNA for AR in a multicenter,
prospective cohort study of heart- and lung-transplant patients, recruited through a
consortium of 5 transplant centers in the Washington, DC metropolitan area. The major
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., bronchiolitis
obliterans syndrome (BOS) or chronic allograft vasculopathy (CAV). The exploratory secondary
objectives are: 1) to compare %ccfdDNA characteristics in AMR (antibody-mediated rejection)
and ACR (acute cellular rejection), 2) to study early immunological changes associated with a
significant rise in %ccfdDNA, and 3) to examine changes in microbiome architecture and other
cell-free nucleic acids in rejection.

- INCLUSION CRITERIA:

- Lung and heart transplant candidates

- Subjects who have undergone lung or heart transplants within 3 months of
transplantation.

- 18 years and older

- Able to understand and willing to sign the informed consent form

EXCLUSION CRITERIA:

-Pregnancy