First immune-evading cells created to treat typediabetes

Date:
August 19, 2020
Source:
Salk Institute
Summary:
Scientists have made a major advance in the pursuit of a safe and
effective treatment for type 1 diabetes, an illness that impacts
an estimated 1.6 million Americans with a cost of $14.4 billion
annually.

Using stem cell technology, researchers generated the first human
insulin-producing pancreatic cell clusters able to evade the
immune system. These 'immune shielded' cell clusters controlled
blood glucose without immunosuppressive drugs once transplanted
in the body.



FULL STORY ==========================================================================
Salk Institute scientists have made a major advance in the pursuit of a
safe and effective treatment for type 1 diabetes, an illness that impacts
an estimated 1.6 million Americans with a cost of $14.4 billion annually.


========================================================================== Using stem cell technology, Salk researchers generated the first human
insulin- producing pancreatic cell clusters able to evade the immune
system, as detailed in the journal Nature on August 19, 2020. These
"immune shielded" cell clusters controlled blood glucose without immunosuppressive drugs once transplanted in the body.

"Most type 1 diabetics are children and teenagers," says Salk Professor
Ronald Evans, senior author and holder of the March of Dimes Chair
in Molecular and Developmental Biology. "This is a disease that is
historically hard to manage with drugs. We hope that regenerative medicine
in combination with immune shielding can make a real difference in the
field by replacing damaged cells with lab-generated human islet-like
cell clusters that produce normal amounts of insulin on demand."
Type 1 diabetes is a lifelong condition that is challenging to manage,
even with automated devices that deliver insulin to regulate blood sugar.

Transplants of pancreatic beta islets--clusters of cells that make
insulin and other hormones--from donor tissue can provide a cure, but
require patients to take life-long immunosuppressing drugs, which carry
serious risks. For decades, researchers have sought a better way to
replenish lost pancreatic cells. Now, device-free transplantation of insulin-producing cells like these brings us a step closer to curing
the disease, according to the lab.

In a previous study, the Evans lab overcame an impediment in the field,
in which stem-cell-derived beta-like cells produced insulin, but were not functional. The cells did not release insulin in response to glucose, as
they were simply under powered, according to Evans. His team discovered
a genetic switch called ERR-gamma that when flipped, "turbo-charges"
the cells.

"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." A critical part of the new study
was to develop a way to grow beta-like cells in a three-dimensional
environment that approximates the human pancreas. This gave the cells
an islet-like property. Importantly, the team discovered that a protein
called WNT4 was able to turn on the ERR-gamma-driven maturation switch.

This combination of steps generated functional cell clusters that mimic
human islets: so-called human islet-like organoids (HILOs).

Next the team tackled the complex issue of immune rejection. Normal
tissue transplants require lifelong immune suppressive therapies to
protect the tissue from being attacked by the immune system; however
these therapies also increase the risk for infections. Inspired by the successes of immunotherapy drugs for cancer, the team initially showed
that the checkpoint protein PD-L1 protected the transplanted cells. "By expressing PD-L1, which acts as an immune blocker, the transplanted
organoids are able to hide from the immune system," says first author
Eiji Yoshihara, a former staff scientist in the lab.

Yoshihara 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 provided sustained blood glucose control
in diabetic mice with healthy immune systems.

"This is the first study to show that you can protect HILOs from the
immune system without genetic manipulation," Downes explains. "If we
are able to develop this as a therapy, patients will not need to take immune-suppressing drugs." More research needs to be done before this
system can be advanced to clinical trials. The transplanted organoids
need to be tested in mice for longer periods of time to confirm that
their effects are long-lasting. More work needs to be done to ensure they
would be safe to use in humans as well. "We now have a product that could potentially be used in patients without requiring any kind of device,"
Evans concludes.


========================================================================== Story Source: Materials provided by Salk_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Eiji Yoshihara, Carolyn O'Connor, Emanuel Gasser, Zong Wei, Tae
Gyu Oh,
Tiffany W. Tseng, Dan Wang, Fritz Cayabyab, Yang Dai, Ruth T. Yu,
Christopher Liddle, Annette R. Atkins, Michael Downes, Ronald
M. Evans.

Immune-evasive human islet-like organoids ameliorate
diabetes. Nature, 2020; DOI: 10.1038/s41586-020-2631-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200819110923.htm

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