Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi shared the Nobel prize for their work on peripheral immune tolerance, a process that is key to organ transplants and treatment of autoimmune diseases
This story has been updated.
Mary E. Brunkow, Fred Ramsdell and Shimon Sakaguchi jointly won the prize, which was announced on Monday in Stockholm. Sakaguchi is a distinguished professor at the Immunology Frontier Research Center at Osaka University in Japan. Brunkow is now a senior program manager at the Institute for Systems Biology in Seattle and Ramsdell is a scientific advisor for Sonoma Biotherapeutics in San Francisco. The Nobel Committee recognized the awardees’ body of work for spurring clinical trials on potential new treatments, such as therapies that may propagate immune cells called regulatory T cells that can suppress overreactive immune responses in an autoimmune disease or organ transplant.
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“Only three people can be recognized for the Nobel Prize, but there are so many pioneers who worked on this,” says Maria-Luisa Alegre, a professor of medicine at the University of Chicago. Her lab specializes in T cell responses during organ transplantation. The Nobel recognition “gives us a lot of further momentum in trying to develop therapies for transplantation as well as for autoimmunity. I’m just thrilled, really, that this is the field that has been chosen.”
Around the 1970s scientists first proposed that there might be a distinct population of T cells that can suppress the immune response. It was thought that such T cells, dubbed suppressor T cells at the time, could potentially unlock a new understanding of the immune system—and of autoimmune disease. Early experiments trying to prove the existence of these cells came up empty handed, however; the theory was ultimately abandoned as being too fringe.
The discovery of CD25, first detailed in a key 1995 paper in the , helped Sakaguchi establish the new class of T cells, which he dubbed regulatory T cells.
In Washington State, Brunkow and Ramsdell further cemented the role of regulatory T cells in immune system activity through several papers in 2001 that looked into the cells’ genetic underpinnings. The two scientists were both then researchers at Celltech Chiroscience, a biotech company that focused on developing autoimmune disease therapies.
To find out whether these peacekeeper cells were a unique lineage of T cells or just a transient population, Ramsdell and Brunkow studied scurfy mice—a strain of mice unexpectedly born with scaly, crusty skin and swollen lymph nodes that lived for just a few weeks. By analyzing genes in healthy and scurfy mice, the team pinpointed a mutant gene called FOXP3 as the key gene responsible for autoimmunity in the diseased mice. The researchers later found that mutations in this gene also caused a severe autoimmune disease, IPEX (short for immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), in humans. These genetic findings laid the groundwork for Sakaguchi and researchers at other labs, including Alexander Rudensky, who currently heads the immunology program at Memorial Sloan Kettering Cancer Center, to confirm that FOXP3 controlled T regulatory cell development.
“The identification of this gene, FOXP3, was the discovery that changed the field, because now there was a molecular basis for immune regulation by T regulatory cells and immune tolerance,” Bluestone says. “That was the defining moment in the early 2000s when all of a sudden, this became real.”
With these fundamental discoveries “the field was off and running,” Savage says. The findings spurred research groups and companies to tap these cells for new treatments. More than 200 clinical trials on therapies investigating such peripheral immune tolerance are in the works, according to the Nobel Committee members. Savage’s lab is studying the basic function and development of regulatory T cells and has a particular interest in cancer.
Regulatory T cells are very commonly found in cancerous tumors, he says. “They’re thought to dampen the anti-tumor immune response, and so there’s a lot of interest in disabling or depleting these cells in the context of cancer therapy.”
Alternatively, other therapies are being developed to try to put lab-grown or genetically modified versions of these cells to work. For example, regulatory T cells are important in boosting organ transplant tolerance—the body’s ability to accept foreign tissue from a donor without triggering a vicious immune response. Alegre’s team has shown in animal models that eliminating regulatory T cells at the time of transplantation causes the body to lose tolerance and reject the organ. “There are many labs that are trying to reinforce this transplantation tolerance or induce it more effectively by either expanding these regulatory T cells … or engineering regulatory T cells,” she says.
For expansion, the cells can be taken from a transplant recipient and copied in bulk. As they grow, you can make them multiply in response to antigens from the donor tissue, Alegre explains. The regulatory T cells can be reinfused at the time of the transplant or when the recipient is showing signs of organ rejection. Another approach takes regulatory T cells and engineers a chimeric antigen receptor (CAR). These regulatory CAR-T cells can express antibodies that specifically recognize and bind to cells on the transplanted organ, suppressing the immune response to it.
“There’s also research on genetic engineering to correct defects [in FOXP3],” she says. “There are people who have a lot of inflammation in autoimmunity because their regulatory T cells are defective because of mutations in this master regulator.”
Bluestone says that researchers have also been working for the past couple decades on a regulatory T cell therapy that could effectively “shut down unwanted autoimmune responses” for diseases such as rheumatoid arthritis or type 1 diabetes.
Sonoma Biotherapeutics is “in the clinic now, as are a couple of other companies, trying to prove the efficacy of this new class of drugs,” he says. “I think there is a lot of excitement now about being able to harness the cells themselves as immunotherapies or drugs that will enhance the function of these cells.”
The team at Sonoma Biotherapeutics is planning on presenting data from its clinical trial of regulatory CAR-T cells in people with rheumatoid arthritis at the , Bluestone says.
“I used to think that some sort of reward may be forthcoming,” Sakaguchi said in a press conference Monday, according to Reuters, “if what we have been doing will advance a little further and it will become more beneficial to people in clinical settings.
Lauren J. Young is an associate editor for health and medicine at Scientific American. She has edited and written stories that tackle a wide range of subjects, including the COVID pandemic, emerging diseases, evolutionary biology and health inequities. Young has nearly a decade of newsroom and science journalism experience. Before joining Scientific American in 2023, she was an associate editor at Popular Science and a digital producer at public radio’s Science Friday. She has appeared as a guest on radio shows, podcasts and stage events. Young has also spoken on panels for the Asian American Journalists Association, American Library Association, NOVA Science Studio and the New York Botanical Garden. Her work has appeared in Scholastic MATH, School Library Journal, IEEE Spectrum, Atlas Obscura and Smithsonian Magazine. Young studied biology at California Polytechnic State University, San Luis Obispo, before pursuing a master’s at New York University’s Science, Health & Environmental Reporting Program.
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