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Researchers develop first functional, lab-generated islets that evade immune system attack

Scientists have developed functional human islet-like organoids (HILOs) that can be shielded from immune system attack, an advance that allowed these HILOs to treat a mouse model of type 1 diabetes for weeks without immunosuppressive drugs. Pancreatic islet dysfunction can compromise the body’s ability to maintain healthy blood glucose (sugar) levels. In type 1 diabetes, the immune system plays a key role in this dysfunction, destroying insulin-producing β (beta) cells in the islets. Transplanting healthy, insulin-producing islets into people with diabetes can help manage blood glucose levels without the need for insulin injections, but several major issues keep this procedure from being routinely used. One hurdle is that limited amounts of cadaveric islets of transplantable quality are available. Another issue is that immunosuppressant drugs that can cause serious side effects must be used to prevent transplant rejection. However, making human islet- like cell clusters in the lab that both mimic healthy islets and evade the immune system has proven to be challenging.

Now, a group of scientists has identified physical and biological factors needed to produce functional, immune-evading HILOs. Building on previous research, they grew β-like cells derived from human induced pluripotent stem cells in a gel-like, three-dimensional scaffold that more closely mimics the human pancreas. These growing conditions produced mature cell clusters that had many of the characteristics of healthy islets, including producing insulin in response to glucose and reducing blood glucose levels in a mouse model of type 1 diabetes. But how could these HILOs be protected from immune attack? Previous work had suggested that a protein called PD-L1 helps shield islets from the immune system. When the scientists treated HILOs to induce PD-L1 production, these HILOs were protected from immune attack when transplanted into a mouse model of type 1 diabetes. Even when transplanted into a mouse model engineered to have a human-like immune system, the HILOs provided steady blood glucose control for over 50 days without the need for immunosuppression.

More research is needed to clarify how long the HILOs’ immune protection can last and how long they can remain functional when transplanted. These issues and others are key to determining whether HILOs can be used to manage blood glucose levels in people with diabetes. Overall, these findings give hope that it may one day be possible to protect transplanted islets in the human body from immune attack. Such advances could lead to improved treatments that free people with type 1 diabetes from the need for insulin injections without incurring the risks of immunosuppression.

Yoshihara E, O’Connor C, Gasser E,…Evans RM. Immune-evasive human islet-like organoids ameliorate diabetes. Nature 586: 606- 611, 2020.

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