How genetic sequencing can help treat rejected transplants

Goel, M., Eugster, A., Schetelig, J. et al. Potential of TCR sequencing in graft-versus-host disease. Bone Marrow Transplant 58, 239–246 (2023). https://doi.org/10.1038/s41409-022-01885-2

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established procedure for the treatment of hematological diseases such as high-risk acute leukemia, myelodysplastic syndromes, and lymphomas. The procedure involves the transfer of hematopoietic stem cells (HSCs) obtained from a related or unrelated donor to the patient. However, one of the major complications of allo-HSCT is graft-versus-host disease (GvHD), which occurs when the donor T cells recognize the recipient’s cells as foreign and mount an immune response against them. GvHD can be life-threatening and affects up to 50% of patients who undergo allo-HSCT.

T cells are a type of immune cell that play a key role in the development of GvHD. T cells recognize foreign substances, such as viruses and bacteria, by their antigen receptors, which are called T cell receptors (TCRs). Each TCR has a variable and a constant section, and the variable section changes based on the rearrangement of genes and the addition and deletion of nucleotides. This allows T cells to recognize and interact with antigens presented by major histocompatibility complex (MHC) molecules on the surface of cells.

In healthy individuals, the TCR repertoire is relatively stable, with a diverse range of TCRs present in the body to detect and eliminate foreign invaders. However, after allo-HSCT, the TCR repertoire undergoes significant changes as the donor T cells reconstitute the patient’s immune system. These changes can be monitored by analyzing the TCR repertoire using next-generation sequencing techniques.

Recent studies have shown that TCR sequencing can provide valuable insights into the development of GVHD. For example, by analyzing the TCR repertoire in patients with GVHD, researchers have identified specific TCR clones that are associated with the development of GVHD. These clones can be tracked over time to gain a better understanding of the underlying mechanisms of GVHD and to develop more effective treatment strategies.

One of the challenges of TCR sequencing is the vast diversity of the TCR repertoire, which can make it difficult to identify specific clones associated with GVHD. However, advances in sequencing technology and bioinformatics have made it possible to overcome these challenges and identify clinically relevant TCR clones. For example, single-cell sequencing can be used to analyze the TCR repertoire at the single-cell level, providing greater resolution and accuracy in identifying specific clones.

Another potential application of TCR sequencing is in the diagnosis of GVHD. Currently, the diagnosis of GVHD relies on clinical symptoms and histological examination of tissue biopsies, which can be invasive and have limited sensitivity and specificity. TCR sequencing could provide a less invasive and more accurate diagnostic tool for GVHD, as changes in the TCR repertoire can be detected in blood samples.

In addition to diagnosis and monitoring, TCR sequencing may also have therapeutic implications for GVHD. For example, by identifying specific TCR clones associated with GVHD, it may be possible to develop targeted therapies that selectively eliminate these clones while sparing the rest of the T cell repertoire.

In conclusion, TCR sequencing has the potential to be a valuable tool in the diagnosis, monitoring, and treatment of GVHD. As research in this area continues to advance, it is likely that TCR sequencing will become an increasingly important part of clinical practice in the management of GVHD.

Summarised by Anoushka Shah