A new study is bringing molecular precision to one of the most difficult problems in transplantation: understanding why a transplanted heart can appear similar under the microscope yet behave very differently inside the patient. Researchers at Vanderbilt Health and the Translational Genomics Research Institute (TGen) have used image-based spatial transcriptomics to map gene activity across heart biopsy samples collected during rejection and after immunomodulatory treatment. Their findings reveal that cardiac allograft rejection is not a single biological event, but a diverse and shifting process involving multiple cell types and molecular programs.
The study, published Aug. 10 in Nature Cardiovascular Research, examined longitudinal endomyocardial biopsies from 49 adult and 13 pediatric heart transplant recipients. The samples were collected during routine surveillance or when rejection was suspected, and included tissue obtained before and after different immunomodulatory therapies. By linking the location of gene expression to the individual cells and structures within the tissue, the researchers were able to investigate patterns that conventional histology cannot resolve.
Heart transplant rejection occurs when the recipient’s immune system recognizes the transplanted organ as foreign and launches an attack. Acute rejection can develop even when patients have few or no symptoms, while severe cases may progress rapidly to impaired heart function and cardiogenic shock. Clinicians typically monitor patients through repeated endomyocardial biopsies, in which small pieces of heart muscle are removed and examined for characteristic signs of immune injury. Although this approach remains central to care, the study’s investigators say that histologic grading does not fully capture the biological variation taking place within the graft.
“Histologic rejection grades” are based largely on the amount and appearance of immune-cell infiltration and tissue damage observed by pathologists. However, patients assigned the same grade may have very different clinical trajectories. Some respond quickly to modest treatment, while others require intensive immunosuppression or continue to deteriorate. This variability can make treatment decisions difficult. Excessive immunosuppression increases the risk of infection, malignancy and drug toxicity, whereas insufficient treatment may allow rejection to progress unnoticed.
Spatial transcriptomics addresses this problem by measuring RNA molecules in their original tissue context. RNA is produced when genes are activated, providing a molecular snapshot of what cells are doing at a particular moment. In image-based spatial transcriptomics, tissue sections are processed so that gene-expression signals can be connected to microscopic features and mapped at subcellular resolution. Rather than simply counting immune cells, researchers can determine which genes are active in specific cell populations and where those molecular programs are concentrated within the transplanted heart.
The Vanderbilt-TGen team found that acute rejection involves a broad network of cellular participants, including immune and cardiac tissue populations. The molecular signatures varied substantially between different types of rejection and even among biopsies assigned the same histologic grade. This hidden heterogeneity may explain why patients with apparently comparable pathology can experience dramatically different symptoms and treatment responses. The results suggest that the tissue’s molecular state may provide a more detailed measure of rejection activity than microscopy alone.
The researchers also identified differences in baseline gene-expression profiles between patients who responded to immunomodulatory therapy and those who did not. These patterns could eventually support predictive biomarkers—molecular indicators that help clinicians estimate whether a patient is likely to benefit from a particular treatment before therapy begins. Such a strategy could move transplant medicine away from a largely reactive model, in which treatment is adjusted after rejection becomes evident, toward a more individualized approach based on the biology of each graft.
The study further connected cell-specific gene-expression programs to cardiac allograft vasculopathy, or CAV. CAV is a form of chronic rejection in which the blood-vessel walls supplying the transplanted heart gradually thicken and narrow. Unlike ordinary coronary artery disease, CAV can affect the entire vascular network of the graft, making it difficult to treat and often limiting long-term transplant survival. The investigators found that genes associated with CAV were detectable in biopsy samples and were also expressed in tissue from patients with end-stage disease severe enough to require a second heart transplant.
“These molecular patterns may offer an early warning system for chronic graft injury,” said Kaushik Amancherla, MD, MSCI, assistant professor of medicine at Vanderbilt Health and co-first author. The research team described the dataset as a resource for future work on acute rejection diagnosis, treatment-response prediction and risk stratification for CAV. Nicholas Banovich, PhD, vice president of scientific development and professor at TGen, said that studies of this kind could help drive biomarker and drug discovery aimed at extending the life of transplanted organs.
The work was conducted through a multidisciplinary collaboration involving transplant physicians, pathologists, computational scientists and genomics researchers. Angela Oill, PhD, a computational scientist at TGen, was co-first author, while Ravi Shah, MD, and Banovich served as co-corresponding senior authors. Tissue samples were collected at Vanderbilt Health between December 2017 and January 2023. The Vanderbilt Transplant Center, the leading U.S. center by solid-organ transplant volume, performed a record number of heart transplants in 2024 and exceeded that total again in 2025. The researchers emphasize that spatial transcriptomics is not yet a replacement for biopsy interpretation, but its ability to reveal cell-specific molecular behavior could help transform how rejection is detected and managed. With further validation in larger patient groups, these signatures may ultimately allow transplant teams to identify dangerous rejection earlier, select therapies more precisely and recognize patients at greatest risk of chronic graft failure.
Subject of Research: People
Article Title: Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics
News Publication Date: 10-Aug-2026
Web References: https://www.nature.com/articles/s44161-026-00849-9; https://www.tgen.org/
References: Nature Cardiovascular Research, DOI: 10.1038/s44161-026-00849-9
Keywords
Heart transplantation, cardiac allograft rejection, acute rejection, chronic rejection, cardiac allograft vasculopathy, spatial transcriptomics, gene expression, transcriptomics, immunomodulatory therapy, precision medicine, transplant medicine, endomyocardial biopsy
Tags: cellular diversity in transplant rejectioncellular programs in heart rejectiongene activity mapping in cardiac tissueheart transplant rejectionimmune response in heart transplantimmunomodulatory therapy effects on rejectionlongitudinal heart biopsy studiesmolecular mechanisms of transplant rejectionmolecular signatures of transplant rejectionprecision medicine in heart transplantationspatial transcriptomics in heart transplantationtissue-specific gene expression analysis
