Microgel immuno-acceptance method could improve pancreatic islet
transplant success

Date:
August 31, 2020
Source:
Georgia Institute of Technology
Summary:
Researchers have developed a new microgel drug delivery method that
could extend the effectiveness of pancreatic islet transplantations
-- from several years to possibly the entire lifespan of a
recipient.



FULL STORY ========================================================================== Pancreatic islet transplants, which revive insulin production to treat
type 1 diabetes, only last an average of three years.


==========================================================================
By learning from a groundbreaking cancer treatment strategy based on a
recent Nobel Prize-winning discovery, researchers at the Georgia Institute
of Technology and University of Missouri developed a new microgel drug
delivery method that could extend the effectiveness of pancreatic islet transplantations -- from several years to possibly the entire lifespan
of a recipient.

Working across multidisciplinary teams using an animal model, the labs
of Professors Andre's Garci'a at Georgia Tech and Haval Shirwan at the University of Missouri have developed a new biomaterial microgel that
could deliver safer, smaller, and more cost-effective dosages of an immune-suppressing protein that could lead to better long-term acceptance
of islet transplantations within the body.

The study was published August 28, 2020, in the journal Science
Advances. The research was led by Maria Coronel, a postdoctoral fellow
in the lab of Garci'a, the Parker H. Petit Chair and executive director
of the Petit Institute for Bioengineering and Bioscience. Garci'a is
also a Regents Professor in the George W. Woodruff School of Mechanical Engineering.

In 2018, the Nobel Prize for medicine was awarded for discovering
how cancer cells send molecular signals to suppress immune response,
thus hiding and protecting those cancer cells from the body's immune
system. Researchers soon developed pioneering treatment methods to signal
and "turn on" the immune system (such as T cells) so the invading cancer
would once again be recognized, allowing a patient's own immune system
to more effectively eliminate their cancer cells.

"The work we are doing is taking a page from that discovery and
using immunotherapy in the opposite sense used by cancer treatments
to control and 'turn off' an immune response to transplant a graft,"
Coronel said. "When you get a transplant, like an islet transplant
or organ transplant, even if it's matched, you will have an immune
response to that graft, and your immune system will recognize it as
non-self and will try to reject and attack the site of the graft."
After islet transplant surgery, traditional postoperative treatments use immune-suppressing systemic drugs that affect the entire body, and can be
toxic -- creating numerous, unwelcome side effects, whose severity often
limits the number of candidates for islet and other organ transplants.



==========================================================================
"A unique aspect of our method is that we have greatly reduced the
dosage needed, which will significantly reduce or eliminate side effects currently caused by today's systemic drug treatments," said Coronel.

The research team developed a new "immune-acceptance" method, which
inserts an engineered biomaterial -- in this case a microgel -- with
the islets at the time of the transplantation. The microgels, which
resemble clusters of micro- sized fish eggs, held and delivered a protein (SA-PD-L1) to a specific transplant area that successfully signaled the
immune system to hold back an immune response, protecting a transplanted
islet graft from being rejected.

This locally delivered molecular signal, using SA-PD-L1, was designed
to quietly suppress any immune response and was effective for up to 100
days with no additional systemic immune-suppressing drug intervention.

"We wanted to use PD-L1 for the prevention of allogeneic islet graft
rejection by simulating the way tumor cells use this molecule to evade
the immune system, but without resorting to gene therapy," said Shirwan, professor of child health and molecular microbiology and immunology at
the University of Missouri School of Medicine.

To achieve this goal, Shirwan worked with Esma Yolcu, professor of child health, also at the University of Missouri School of Medicine. Both
were previously at the University of Louisville, where they generated
the SA-PD-L1, a novel form of the molecule that can be positionally
displayed on the surface of islet grafts or microgels for delivery to
the graft site.

"Microgels presenting SA-PD-L1 represent an important technological
development that has potential not only for the treatment of type 1
diabetes, but also other autoimmune diseases and various transplant
types," Shirwan said.

In addition to engineering this specific biomaterial microgel, the team
tested its lifespan durability and dosage release possibilities. They
also looked at its longer-term effects on both the graft and the immune response and function of the recipient -- evaluating its long-term biocompatibility potential.

"One of the major goals in the diabetes field over the past two decades
has been to allow the immune-acceptance of grafts and avoid the toxic
drugs used to induce immune suppression, which affect the entire body,"
Garci'a said.

"Generally speaking, organ transplantation is very successful at dealing
with a variety of chronic conditions. These are very exciting results
as proof of principle that demonstrate this engineered biomaterial and procedure may provide a platform technology that is applicable to other transplantation settings and may enlarge the pool of candidates who can
safely receive transplants."

========================================================================== Story Source: Materials provided by
Georgia_Institute_of_Technology. Original written by Walter Rich. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Mari'a M. Coronel, Karen E. Martin, Michael D. Hunckler, Graham
Barber,
Eric B. O'Neill, Juan D. Medina, Enrico Opri, Claire
A. McClain, Lalit Batra, Jessica D. Weaver, Hong S. Lim, Peng
Qiu, Edward A. Botchwey, Esma S. Yolcu, Haval Shirwan, Andre's
J. Garci'a. Immunotherapy via PD-L1- presenting biomaterials leads
to long-term islet graft survival. Science Advances, 2020; 6 (35):
eaba5573 DOI: 10.1126/sciadv.aba5573 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200831112336.htm

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