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Two paths to a cure: Researchers use immunology and cell therapy to tackle type 1 diabetes

University of Minnesota diabetes researchers Pratima Pakala, Ph.D., and Brian Fife, Ph.D. Photo by Scott Streble University of Minnesota researcher Pratima Pakala, Ph.D., knows the struggles of people living with diabetes. “My dad has been diabetic ever since I remember,” she says. “I understand the hardships of patients and what families go through.”

Pakala, who grew up in Varanasi, India, says that in her native culture people commonly believed that diabetes was the result of bad luck.When she learned in school that diabetes has a scientific basis, it changed her life’s path. “It wasn’t that he was unlucky or drew the short stick,” she says of her father and his diabetes. “There were cells involved. We can do something about it,” she recalls learning. “That was so fascinating.”

That realization propelled Pakala into a career searching for a cure for type 1 diabetes—for her father and others. Her University colleague professor Brian Fife, Ph.D., also has a family connection to diabetes through uncles and cousins and is fascinated by the disease. “I’ve always been interested in how the body determines what is self and what is foreign,” says Fife, an immunologist. In diabetes, he explains, the T-cells attack and destroy the body’s own insulin-producing islet cells in the pancreas.

University researchers are focused on a number of promising ways to cure type 1 diabetes: through pig and stem cell islet transplantation and immune-cell regulation.

Despite their shared interest, however, Pakala and Fife are taking distinctly different approaches to preventing diabetes and finding a cure.

Pakala is seeking ways to make islet transplants safer for patients who already have diabetes, and Fife is working to “turn off” destructive immune cells that lead to type 1 diabetes to reverse or prevent the disease.

Making immunosuppressives obsolete

Pakala, a member of the University’s Schulze Diabetes Institute (SDI), is focused on therapies that would allow patients who have had islet transplants to avoid taking immunosuppressive drugs.

Such drugs are used post-transplant to stop the immune system’s attack on transplanted islets, but they can cause serious side effects, and they are toxic to the body over time. Eventually, they attack islet cells.

“People are really afraid of immunosuppressive drugs. That’s why [some] people who would benefit from transplants opt out,” she says.

Pakala is developing a therapy that involves taking patients’ blood, purifying the regulatory T cells, growing the cells in large quantities, and transplanting the new cells along with the islets. “Regulatory T-cells will suppress a transplant rejection,” she explains, adding that they are also non-toxic and don’t need to be taken daily like immunosuppressive drugs.

For nearly three years, Pakala has worked on this National Institutes of Health-funded project and last year began testing the treatment in animal models. “Once we can prove that it works, we can use this same approach for pig and human islets,” she says.

Pakala, who believes the approach will work for other types of transplants as well, says that she hopes to begin testing in humans in the next two to three years. “This is a safer and more targeted approach that would allow islet transplants without chemical agents,” she says.

Turning off diabetes

Fife’s work also focuses on T-lymphocytes, but in a different way.

Since 2002, he has used diabetic mice to investigate aberrant T-cell activity in type 1 diabetes and better understand the mechanisms of the disease. Fife labels the T-cells red and then uses a powerful microscope to track their activity in the lymph nodes and pancreas. This monitoring helped him to develop a treatment to reverse diabetes in mice, with the goal of applying the technique to humans.

“We want to find these renegade T-cells that cause diabetes and turn them off. Using this approach, we can silence disease-causing cells, leaving the immune system intact—an enormous benefit over total immune suppression,” says Fife, who is a new faculty member of the University’s Department of Medicine and the Center for Immunology.

To cure diabetes, he believes researchers need to not only manage the immune response, but also replace the lost insulin-producing cells.

Fife is collaborating with Meri Firpo, Ph.D., a professor in the University’s Stem Cell Institute and member of the SDI, to find a way to create new islet cells or replace those that have been destroyed.

Fife says that he and Pakala are working toward the same goal. “With a better understanding of how to regulate the immune response against islets,” he says. “We’ll be able to cure diabetes.”

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