Scientists hope to treat type 1 diabetes by disguising stem cells

People have been waiting for a cure for type 1 diabetes for a long time. Dr. Hannah Pizatois one of them.

“I've been told all my life that a cure was coming and that we wouldn't have to deal with this for long, but the cure never showed up,” said Pizzato, the institute's chief scientist. spoke. University of Arizona College of Health Sciences Advanced Molecular Immunotherapy Center.

Mr. Pizzato was diagnosed with type 1 diabetes when he was 4 years old. She was too young to understand that it was an autoimmune disease. She didn't know that her immune system was attacking cells in her pancreas that are responsible for producing insulin, the hormone that regulates blood sugar levels. However, from an early age, she began to wonder why people get sick.

“I've always been interested in the fundamentals of how the body works and adapts over time to keep us alive,” she said . “I became interested in how biology influences human development.”

It is no surprise that her teaching and research trajectory focused on the immune system and type 1 diabetes. She received her PhD from Washington University in St. Louis, where she worked under the supervision of Drs. Dr. Deepta Bhattacharyawas recently appointed as the first Executive Director of CAMI.

In 2017, Pizato followed Bhattacharya to Tucson, where he completed his thesis and became a postdoctoral fellow in his lab at the university. Tucson College of Medicine Department of Immunobiology.

In Bhattacharyya's lab, Pizzato worked on overcoming immune barriers to stem cell transplants. Now, as one of the first scientists to work at CAMI, Pizzato is developing that research with the goal of eventually curing type 1 diabetes using stem cell therapy.

Building towards a cure

Pizzato's interest in the immune system led her to be at the forefront of stem cell therapy, a field that is pushing the boundaries of modern medicine. Stem cells are unique in that they are self-renewing and unspecialized. This means that they can transform into different types of cells in the body, including blood, muscle, and brain cells.

Since the first successful bone marrow transplant in 1956, scientists around the world have been researching stem cells and their potential to fight disease, regenerate damaged tissue, and develop personalized treatments for patients. . Currently, hematopoietic stem cells found in bone marrow are used to treat blood cancers such as leukemia, lymphoma, and multiple myeloma.

One of the fastest growing areas of stem cell research utilizes pluripotent stem cells, which are cells that can transform into any type of cell in the body.

“We study pluripotent stem cells because they can differentiate into other types of cells that perform specialized functions,” Pizzato said. “Theoretically, these stem cells could be transformed into anything a patient needs. For example, our goal is to mature the stem cells into insulin-producing beta cells, which can then be used in patients with type 1 diabetes. By transplanting them, we will be able to replenish the beta cells they have lost and reverse the disease.”

The biggest challenge to stem cell therapy comes from the body's natural protector against invaders, the immune system. This complex network of cells, tissues, and organs fights infections, diseases, and, unfortunately, regenerative treatments, including stem cells.

“Just as the body's immune system rejects a kidney transplant, the body will reject stem cells without the help of immunosuppressants,” Pizato explained. “However, lifelong immunosuppression increases the risk of infection and may even lead to an inability to suppress the formation and proliferation of cancer cells.”

Bhattacharyya and Pizzato have spent years trying to find a solution to this problem. Now they may be on the brink of a breakthrough.

“We think that by modifying stem cells in a way that hides them from the immune system, we can avoid the need for immunosuppression and potentially create truly effective treatments,” Pizzato said.

Develop technology to disguise stem cells

Pizzato was the first author of the paper published in . stem cell report At the beginning of this year. In the study, the researchers genetically engineered stem cells to evade detection by various parts of the immune system, including T cells.

T cells, a type of white blood cell, are a major factor in immune rejection. They are constantly scanning for things that don't exist in your body, such as viruses and bacteria. T cells also perform security checks on other cells by checking for human leukocyte antigen, a protein on the surface of most cells. If the protein does not match a specific human white blood cell antigen in the body, T cells are triggered to kill the cell.

“The human leukocyte antigen on the transplanted cells is the absolute proof to the T cells that they are not part of the body,” she says. “To get around this problem, we used genetic engineering tools to cut out the gene that encodes that protein. It acts as a camouflage.

The lack of human leukocyte antigens solved the T-cell problem, but it did not address two other parts of the immune system: natural killer cells and complement deposition. Natural killer cells, like T cells, are constantly on alert to destroy damaged or diseased cells. The immune system also relies on a process called complement deposition, in which specific proteins bind to the surface of an invader to help the immune system recognize the threat.

After removing the human leukocyte antigen, Pizzato said the research team added several other proteins, some of which send inhibitory signals that interfere with natural killer cells, and others that prevent complement deposition. said.

“It's like taking off the stem cell glasses and adding a hat, fake beard, and coat to avoid being recognized,” Pizzato said.

The engineered stem cells were tested in mice with fully functional immune systems and successfully avoided rejection by the immune system and persisted.

“These findings are very encouraging and give us confidence that we are ready to move forward,” Pizzato said.

Move forward with CAMI

In July, Pizzato moved to Phoenix and established the first CAMI lab on the second floor of the Biomedical Partnership Building.

Some of the first experiments Pizzato plans to do include narrowing down the number of modifications needed to successfully hide stem cells from the normal immune system. Ultimately, she and Bhattacharyya hope to test the genetically engineered stem cells in a non-obese diabetic mouse model of type 1 diabetes and translate the mouse research into human findings.

“This is a particularly important step and will be a huge challenge for engineered stem cells,” Pizzato said. “Type 1 diabetes is an autoimmune disease, so the immune system is already primed to be exposed to a hostile environment. The first big step was to create stem cells that are invisible to the immune system, but The invisible, unspecialized stem cells floating around are of no real use to anyone. We turn these invisible stem cells into beta cells, which improve blood sugar levels. We want to help you adjust.”

For Pizzato, CAMI helps bridge the gap between her research and potential products. It may even help you realize your lifelong dream.