Teaching the immune system a new trick could one day level the organ transplant playing field

A Medical University of South Carolina team reports in Frontiers in Immunology that it has engineered a new type of genetically modified immune cell that can precisely target and neutralize antibody-producing cells complicit in organ rejection. Similar strategies have been used to stimulate the immune system against certain cancers, but Ferreira’s team is the first to show its utility in tamping down immune responses that can lead to organ rejection.

More than 50,000 organ transplants take place each year in the U.S. While often lifesaving, these procedures depend on a precise match between donor and recipient genes to avoid rejection. When the immune system detects foreign tissue, it can attack the transplanted organ.

For decades, doctors have used immunosuppressant drugs to lower the risk of rejection. But these drugs work broadly, suppressing the entire immune system. This can lead to side effects and shorten the life of the transplanted organ.

The MUSC team, led by Leonardo Ferreira, Ph.D., an assistant professor of Pharmacology and Immunology, showed the feasibility of targeted immunosuppression after transplant that could one day reduce rejection without leaving patients vulnerable to infection and other side effects. This strategy could also level the playing field for patients who have limited eligibility for organs because they are especially prone to rejection.

Jaime Valentín-Quiroga, first author of the article and a Ph.D. candidate at University Hospital La Paz in Madrid, Spain, working in the lab of Eduardo Lopez Collazo, Ph.D., is also co-advised by Ferreira. 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 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.”

Balancing the immune system

When in working balance, the immune system protects the body against outside invaders without attacking its own tissues. B-cells release antibodies that attack pathogens and infected cells. Regulatory T-cells, or Tregs, keep the immune response from going too far, preventing tissue damage and autoimmune diseases.

“When you prick your finger, it is important to mount a strong immune response to kill all the bacteria that entered your finger,” Ferreira said. “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 target for B-cells are human leukocyte antigen (HLA) proteins, which help the immune system to tell self from non-self. Doctors try to match donor and recipient HLA proteins as closely as possible, but with more than 40,000 HLA variants, perfect matches are rare.

One variant, HLA-A2, is found in nearly one-third of the global population. Patients who have had previous exposure to HLA-A2 are considered “pre-sensitized,” meaning their immune systems are primed to respond to it and release very large amounts of anti-HLA-A2 antibodies. These include previous transplant patients; women who, during pregnancy, carried a child with HLA-A2 inherited from their partners; and recipients of HLA-A2-positive blood transfusions. Pre-sensitized patients have a much more difficult time finding a compatible donor organ.

The CHAR approach

Ferreira’s team has developed a novel way for the Tregs to find and neutralize specifically the B-cells producing anti-HLA-A2 antibodies. They have fitted the Tregs with a CHAR – short for chimeric anti-HLA antibody receptor – which detects the appropriate B-cells and alerts the Tregs to suppress them. 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. In this way, 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 and prevent it from going overboard.

Ferreira’s team tested the efficacy of CHAR-Tregs in cells from dialysis patients with a history of kidney rejection. The cells showed high levels of anti-HLA-A2 antibodies, but exposure to CHAR-Tregs dramatically decreased 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.”

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