A research team from the Medical University of South Carolina has achieved a significant breakthrough in organ transplantation by developing genetically engineered immune cells that can precisely target and neutralize the antibody-producing cells responsible for organ rejection. The study, published in Frontiers in Immunology, represents the first application of this technology to suppress immune responses in transplant medicine.
The MUSC team, led by Leonardo Ferreira, Ph.D., an assistant professor of Pharmacology and Immunology, has demonstrated the feasibility of targeted immunosuppression that could reduce rejection without leaving patients vulnerable to infections and other complications associated with broad immunosuppressive drugs.
Addressing Critical Transplant Challenges
More than 50,000 organ transplants take place each year in the U.S., with success heavily dependent on genetic compatibility between donor and recipient. When the immune system detects foreign tissue, it can attack the transplanted organ, leading to rejection. For decades, doctors have relied on immunosuppressant drugs that work broadly, suppressing the entire immune system and potentially shortening the life of the transplanted organ.
A key challenge involves human leukocyte antigen (HLA) proteins, which help the immune system distinguish self from non-self. With more than 40,000 HLA variants, perfect matches are rare. Patients who have had previous exposure to specific HLA types, such as HLA-A2 found in nearly one-third of the global population, are considered "pre-sensitized" and face particular difficulties finding compatible donor organs.
"Pre-sensitized patients have a much more difficult time finding a compatible donor organ," the researchers noted. This includes previous transplant patients, women who carried children with HLA-A2 inherited from their partners during pregnancy, and recipients of HLA-A2-positive blood transfusions.
The CHAR-Treg Innovation
The research team developed a novel approach using regulatory T-cells (Tregs) fitted with chimeric anti-HLA antibody receptors (CHARs). These engineered cells can detect and neutralize specifically the B-cells producing anti-HLA-A2 antibodies while preserving broader immune function.
"When CHARs detect and attach to B-cells secreting anti-HLA-A2 antibodies, they alert the Tregs to neutralize these problematic B-cells, essentially signaling the immune system to stand down and not attack the organ," Ferreira explained. "Not only do CHARs act like heat-seeking missiles to find the right B-cells to target, but they also hold the key to the Treg's ignition, activating its machinery to elicit a more precise immunosuppressive response."
The approach leverages the natural balance of the immune system, where B-cells release antibodies against pathogens while Tregs prevent immune responses from causing excessive tissue damage. As Ferreira noted, "When you prick your finger, it is important to mount a strong immune response to kill all the bacteria that entered your finger. But it's also important to bring that immune response to a halt when all the bacteria have been killed."
Clinical Validation in Patient Samples
The team tested CHAR-Tregs using cells from dialysis patients with a history of kidney rejection, which showed high levels of anti-HLA-A2 antibodies. Exposure to CHAR-Tregs dramatically decreased antibody levels, demonstrating efficacy in a clinically relevant context.
"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."
International Collaboration and Future Prospects
The research involved international collaboration, with first author Jaime Valentín-Quiroga, a Ph.D. candidate at University Hospital La Paz in Madrid, Spain, working under the co-advisement of Ferreira and Eduardo Lopez Collazo, Ph.D. López-Collazo's research team provided the patient samples for the study.
"Spain is one of the leading countries worldwide in organ transplantation and offers the perfect platform to move from bench to bedside," said Valentín-Quiroga. "His research combines my favorite topics, fine-tuning the immune system and using cutting-edge biotechnology to enhance immune cells' natural functions."
This targeted immunosuppression strategy could level the playing field for patients who have limited eligibility for organs due to heightened rejection risk, potentially transforming outcomes for thousands of transplant candidates annually. The approach represents a significant advancement from previous applications of similar genetic engineering strategies, which have primarily focused on stimulating immune responses against cancers rather than suppressing them for transplant tolerance.
