CHAR-Tregs: a potential approach for reducing risk of transplant rejection
By targeting and suppressing B cells that produce specific antibodies, a new immunotherapy has shown promise in reducing the immune response associated with organ transplant rejection.
Researchers at the Medical University of South Carolina (SC, USA) have developed a new type of modified immune cell capable of specifically targeting B cells that produce human leukocyte antigen (HLA) antibodies involved in organ transplant rejection. By demonstrating its potential to minimize unwanted immune responses associated with donor transplants, the team has shown, for the first time, the potential of repurposing immune cells to suppress an immune response that contributes to organ rejection.
Organ transplants offer hope to patients in need of a functioning organ when theirs have failed or are no longer functioning properly. However, the body’s immune system is designed to protect against foreign substances, which increases the risk of a donor organ being rejected by the recipient’s body.
The HLA system is one mechanism the body uses to distinguish self from non-self. With over 40,000 HLA variants, it is rare for a patient and donor to share identical HLA profiles, which significantly increases the risk of organ rejection. HLA-A2 is one of the more common HLA antigens, present in approximately one-third of the global population. For patients who do not naturally possess the HLA-A2 antigen but have been previously exposed to it through prior transplants, blood transfusions, or pregnancy, their immune system may have developed anti-HLA-A2 antibodies.
CAR-iNKT: novel immunotherapy for high-risk childhood leukemia
A new immunotherapy that employs invariant natural killer T cells (CAR-iNKTs) shows promise in mouse models of high-risk childhood leukemia, outperforming standard CAR-T treatments.
When these patients who are considered “pre-sensitized” receive an organ from an HLA-A2-positive donor, their pre-existing anti-HLA-A2 antibodies can recognize and bind to the HLA-A2 antigens present on the donor organ. This recognition triggers an immune response against the transplanted tissue, potentially leading to rejection. Immunosuppressant drugs are often administered to combat this; however, they suppress the entire immune system, leaving patients susceptible to infections and other side effects.
To tackle this type of organ rejection, Leonardo Ferreira and his team developed a new type of genetically modified immune cell: chimeric anti-HLA antibody receptor regulatory T-cells (CHAR-Tregs). When the CHAR binds to B cells producing anti-HLA-A2 antibodies, they signal the Tregs to suppress anti-HLA2-A2 antibody production. This approach aims to modulate the immune system by promoting tolerance to targeted allogeneic HLA molecules while preserving immunity to other antigens.
The researchers evaluated their CHAR-Tregs using cells obtained from dialysis patients with a history of kidney transplant rejection. At first, these patient-derived samples exhibited high levels of anti-HLA-A2 antibodies. However, following CHAR-Tregs exposure, the researchers observed a significant decrease in antibody levels.
“We took patients’ cells that have been shown to make an extremely strong response against HLA-A2-expressing cells, and we showed that the novel CHAR-Tregs calmed them down,” said Ferreira. “I think that’s the most exciting part of our study – we show that this strategy works in the cells of actual pre-sensitized patients.”
Although similar strategies like CAR T-cell therapy have been used to stimulate the immune system by targeting specific antigens found on cancer cells, this study is the first to demonstrate its effectiveness in suppressing immune responses that can lead to organ rejection. By selectively targeting B cells producing antibodies again a donor’s HLA type, this approach could help reduce the risk of transplant failure and improve outcomes for patients who are already sensitized to donor tissues.
