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Newly Created Immune-Evading Human Islets Could Potentially Treat Diabetes
Scientists from the Salk Institute have recently reported a major breakthrough in the development of an efficacious therapy for type I diabetes by the use of stem cell technology. They successfully produced the first human insulin-producing pancreatic cell clusters which can evade the host immune system.
By Manish Muhuri, Ph.D.
Type 1 diabetes (T1D) is a lifelong medical condition that makes up an estimated 5–10% of all diabetes cases. Around 1.6 million Americans are living with T1D, including about 200,000 youth. Estimated expenditure of $16 billion is associated with T1D-related healthcare costs and lost income annually (1).
In healthy individuals, the insulin hormone is produced by one of the cell types in pancreatic islets called beta cells. Insulin helps the body use glucose for energy and helps control blood glucose levels. In people with T1D, the body’s immune system attacks and destroys the beta cells. People with T1D must take insulin because their bodies no longer make this hormone. Over time, T1D associated complications can affect major organs in your body, including heart, blood vessels, nerves, eyes, and kidneys.
Pancreatic Islet Transplantation
Type 1 diabetes is usually treated through insulin administration, lifestyle, and dietary changes, but no known cures exist. One of the most promising experimental therapies is pancreatic islet transplantation, where doctors take islets with healthy beta cells from the pancreas of a deceased organ donor and inject them in a patient. These islets begin to make and release insulin in the recipient’s body.
While significant progress has been made in the islet transplantation field, a limited supply of islets and inadequate means for preventing islet rejection by the recipient has hampered its development into an effective therapy. Additionally, patients are required to take life-long immunosuppressing drugs, which carry serious risks.
The first human trials for islet transplantation were carried out in the mid-1980s with a low long term success rate. In the year 2000, Dr. Shapiro’s group in Edmonton, Canada, reported a new protocol whereby seven consecutive participants didn’t need insulin injections for at least 4 months following one, two, or three islet transplantations (2). The lack of high-quality islet donors has also prompted efforts to use reprogrammed stem cells to generate beta cells. Stem cells are the body’s raw materials — cells from which all other cells with specialized functions are generated. Though the major source of stem cells is a three-to-five day old embryo, scientists have successfully transformed regular adult cells into stem cells using genetic reprogramming. These reprogrammed stem cells are also referred to as induced pluripotent stem cells (iPSCs). The lack of high-quality islet donors has also prompted efforts to use stem cells to generate beta cells.
New Research Breakthrough
Dr. Ronald Evan’s group at Salk Institute has made significant advances to generate glucose-responsive human β-cells suitable for transplantation with the potential to substantially improve patients’ lives. Their work was published in a paper titled, “Immune-evasive human islet-like organoids ameliorate diabetes” in Nature (3).
There have been attempts to generate insulin-producing pancreatic beta cells from stem cells to replace those that have been destroyed by the immune system. However, to make the cells responsive to glucose changes and to prevent an immune attack after the cells are transplanted has proven to be a significant challenge.
In a previous study, the Evans lab demonstrated that these beta cells did not release insulin in response to glucose, as they were simply underpowered (4). They discovered that increasing the expression of a receptor called ERR-gamma could give beta-like cells, derived from human- iPSCs, enough energy to mature into functional cells that responded to glucose changes by producing insulin.
In the new study, they grew beta cells in a 3D environment to recapitulate the human pancreas. Evans’ group found that a protein called WNT4 was able to turn on the ERR-gamma-driven maturation of the beta cells. By exploiting that pathway, they built mature, functional, 3D cell clusters—called human islet-like organoids (HILOs)—that restored glucose control in mouse models of diabetes without triggering immune rejection.
“When we add ERR-gamma, the cells have the energy they need to do their job,” says Michael Downes, a Salk senior staff scientist and co-author of both studies. “These cells are healthy and robust and can deliver insulin when they sense high glucose levels.” (5)
Moving further, the team decided to address the limitations rendered by allogenic and autoimmune response against the transplanted beta cells. Given the remarkable successes of cancer immunotherapy drugs, they decided to investigate whether PD-L1 expression would protect HILOs from immune rejection. PD-L1, a known checkpoint that keeps immune reactions in check, was found to be expressed in a subset of cells in the healthy islets.
Yoshihara, the lead author of the study, then developed a method to induce PD-L1 in HILOs with short pulses of the protein interferon-gamma. When transplanted into diabetic mice, these immune-evasive HILOs reduced glucose levels for more than 40 days, whereas the efficacy of cells lacking interferon-gamma treatment decreased, the team reported.
“This is the first study to show that you can protect HILOs from the immune system without genetic manipulation,” comments Michael Downes. “If we are able to develop this as a therapy, patients will not need to take immune-suppressing drugs.”
These are still early days, but regenerative medicine, in combination with immune shielding, can make a real difference in the field. The Salk researchers plan to test the HILOs transplants in mice for more extended periods to confirm their effects and safety before starting a clinical trial. However, studies like these bring us a step closer to curing the disease that is historically hard to manage with drugs.
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