Schematic illustration of chimeric anti-human leukocyte antigen (HLA) antibody receptor (CHAR) that includes a CD28-CD3zeta signaling area, expressed on the floor of a human regulatory T cell (Treg). Credit score: Frontiers in Immunology (2025). DOI: 10.3389/fimmu.2025.1601385
A Medical College of South Carolina workforce stories in Frontiers in Immunology that it has engineered a brand new kind of genetically modified immune cell that may exactly goal and neutralize antibody-producing cells complicit in organ rejection.
Related methods have been used to stimulate the immune system in opposition to sure cancers, however Ferreira’s workforce is the primary to indicate its utility in tamping down immune responses that may result in organ rejection.
Greater than 50,000 organ transplants happen every year within the U.S. Whereas typically lifesaving, these procedures rely upon a exact match between donor and recipient genes to keep away from rejection. When the immune system detects international tissue, it may well assault the transplanted organ.
For many years, docs have used immunosuppressant medication to decrease the danger of rejection. However these medication work broadly, suppressing your complete immune system. This may result in negative effects and shorten the lifetime of the transplanted organ.
The MUSC workforce, led by Leonardo Ferreira, Ph.D., an assistant professor of Pharmacology and Immunology, confirmed the feasibility of focused immunosuppression after transplant that might someday cut back rejection with out leaving sufferers susceptible to an infection and different negative effects. This technique may additionally degree the enjoying subject for sufferers who’ve restricted eligibility for organs as a result of they’re particularly liable to rejection.
Jaime Valentín-Quiroga, first writer of the article and a Ph.D. candidate at College Hospital La Paz in Madrid, Spain, working within the lab of Eduardo Lopez Collazo, Ph.D., can also be co-advised by Ferreira. López-Collazo’s analysis workforce supplied the affected person samples for the examine.
“Spain is one of the leading countries worldwide in organ transplantation and offers the perfect platform to move from bench to bedside,” mentioned Valentin-Quiroga.
“I am lucky to be co-advised by Dr. Ferreira. His research combines my favorite topics, fine-tuning the immune system and using cutting-edge biotechnology to enhance immune cells’ natural functions.”
Dr. Leondo Ferreira of the Medical College of South Carolina takes affected person samples obtained from College Hospital La Paz in Madrid, Spain from a liquid nitrogen tank. Credit score: Medical College of South Carolina, Clif Rhodes
Balancing the immune system
When in working stability, the immune system protects the physique in opposition to exterior invaders with out attacking its personal tissues. B-cells launch antibodies that assault pathogens and contaminated cells. Regulatory T-cells, or Tregs, preserve the immune response from going too far, stopping tissue harm and autoimmune illnesses.
“When you prick your finger, it is important to mount a strong immune response to kill all the bacteria that entered your finger,” Ferreira mentioned. “But it’s also important to bring that immune response to a halt when all the bacteria have been killed. Otherwise, you could lose your finger in the process, and the cure would be as bad as the disease.”
A key goal for B-cells are human leukocyte antigen (HLA) proteins, which assist the immune system to inform self from non-self. Medical doctors attempt to match donor and recipient HLA proteins as carefully as doable, however with greater than 40,000 HLA variants, excellent matches are uncommon.
One variant, HLA-A2, is present in practically one-third of the worldwide inhabitants. Sufferers who’ve had earlier publicity to HLA-A2 are thought-about “pre-sensitized,” which means their immune techniques are primed to reply to it and launch very giant quantities of anti-HLA-A2 antibodies.
These embrace earlier transplant sufferers; girls who, throughout being pregnant, carried a toddler with HLA-A2 inherited from their companions; and recipients of HLA-A2-positive blood transfusions. Pre-sensitized sufferers have a way more tough time discovering a suitable donor organ.
The CHAR strategy
Ferreira’s workforce has developed a novel method for the Tregs to search out and neutralize particularly the B-cells producing anti-HLA-A2 antibodies. They’ve fitted the Tregs with a CHAR—brief for chimeric anti-HLA antibody receptor—which detects the suitable B-cells and alerts the Tregs to suppress them.
When CHARs detect and fix to B-cells secreting anti-HLA-A2 antibodies, they alert the Tregs to neutralize these problematic B-cells, primarily signaling the immune system to face down and never assault the organ. On this method, not solely do CHARs act like heat-seeking missiles to search out the proper B-cells to focus on, however additionally they maintain the important thing to the Treg’s ignition, activating its equipment to elicit a extra exact immunosuppressive response and stop it from going overboard.
Ferreira’s workforce examined the efficacy of CHAR-Tregs in cells from dialysis sufferers with a historical past of kidney rejection. The cells confirmed excessive ranges of anti-HLA-A2 antibodies, however publicity to CHAR-Tregs dramatically decreased antibody ranges.
“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,” mentioned 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.”
Extra data:
Chimeric anti-HLA antibody receptor engineered human regulatory T cells suppress alloantigen-specific B cells from pre-sensitized transplant recipients.v, Frontiers in Immunology (2025). DOI: 10.3389/fimmu.2025.1601385
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Genetically modified immune cell may assist organ transplant sufferers who’re liable to rejection (2025, August 15)
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