The same rejection grade can reflect different processes in a transplanted heart
The same rejection grade can reflect different processes in a transplanted heart
In a study of 62 heart transplant recipients, conventional microscopic biopsy assessment was compared with a map of gene activity in individual cells. Biopsies with the same rejection grade showed different combinations of immune cells, blood vessel cells, and cardiac tissue on this map. Some of these combinations were associated with the response to treatment and subsequent narrowing of the graft vessels.
After a heart transplant, physicians regularly collect a tiny sample of heart muscle called an endomyocardial biopsy. A pathologist examines it under a microscope and assigns a rejection grade. Physicians use this assessment to decide whether to intensify immunosuppression, which consists of drugs that limit the immune attack on the donor organ. A single grade can encompass different combinations of immune cells, blood vessel cells, and cells from the cardiac tissue itself.
In an article published on 10 August, the authors examined 195 tissue samples measuring 0.6 mm in diameter. They measured the activity of 477 preselected genes in 162 638 cells and identified 28 cell types. Spatial transcriptomics shows which of these genes are active in each cell and where that cell is located within the tissue section. This makes it possible to distinguish the immune cells involved in the attack, blood vessel cells, and cardiac muscle cells around an inflamed area.
The authors first compared these cellular states with conventional histological grades. They then compared biopsies collected before and after antirejection therapy and tested some of the observed differences in an external biopsy cohort. The study design and samples are available in a public dataset.
Among 32 patients with cellular rejection, in which T cells have the primary role, rejection resolved after therapy in 15 patients and persisted in 17. Before treatment, the second group had higher activity of genes associated with T-cell activation and tissue remodeling. Within this group, the same microscopic grade corresponded to different tissue states and different courses of rejection after therapy.
The authors also examined how these states were related to cardiac allograft vasculopathy, which is the gradual narrowing of blood vessels in the donor heart. In biopsies collected during and after rejection episodes, they identified cell-specific genes associated with the subsequent development of this condition, particularly in vascular cells and supporting tissue. In a separate set of hearts with severe vasculopathy, the same genes were expressed in similar cell types.
A conventional grade describes the damage visible in a small tissue sample. A molecular map can show which cells contribute to that damage and how their states are associated with the subsequent course of rejection.