Regeneration of insulin-producing islets
may lead to diabetes cure
Animal study finds spleen produces
adult precursor cells, may have broader application
here for more information about MGH diabetes research
BOSTON - November 13, 2003 - Cells from an unexpected source,
the spleen, appear to develop into insulin-producing pancreatic
islet cells in adult animals. This surprising finding from Massachusetts
General Hospital (MGH) researchers, published in the Nov. 14 issue
of Science, is a followup to the same team's 2001
report of a treatment that cures advanced type 1 diabetes in
mice. In discovering the biological mechanism behind that accomplishment,
the researchers also have opened a potential new approach to replacing
diseased organs and tissues using adult precursor cells.
"We have found that it is possible to rapidly regrow islets
from adult precursor cells, something that many thought could not
be done," says Denise Faustman, MD, PhD, director of the MGH
Immunobiology Laboratory and principal investigator of the study.
"By accomplishing effective, robust and durable islet regeneration,
this discovery opens up an entirely new approach to diabetes treatment."
David M. Nathan, MD, director of the MGH
Diabetes Center, notes, "These exciting findings in a mouse
model of type 1 diabetes suggest that patients who are developing
this disease could be rescued from further destruction of their
insulin-producing cells. In addition, patients with fully established
diabetes possibly could have their diabetes reversed." Nathan
has developed a protocol to test this approach in patients, but
additional grant support is needed before a clinical trial can begin.
Type 1 diabetes develops when the body's immune cells mistakenly
attack the insulin-producing islet cells of the pancreas. As islet
cells die, insulin production ceases, and blood sugar levels rise,
damaging organs throughout the body. In their earlier study, Faustman's
team directly attacked this process by retraining the immune system
not to attack islet cells. They first used a naturally occurring
protein, TNF-alpha, to destroy the mistargeted cells. Then they
injected the mice with donor spleen cells from nondiabetic mice.
A protein complex on these cells plays a key role in teaching new
immune cells to recognize the body's own tissues, a process that
goes awry in diabetes and other autoimmune disorders.
The researchers expected to follow that process, which eliminated
the autoimmune basis of the animals' diabetes, with transplants
of donor islet cells. However, they were surprised to find that
most of the mice did not subsequently need the transplant: Their
bodies were producing normal islet cells that were secreting insulin.
"The unanswered question from that study was whether this was
an example of rescuing a few remaining islet cells in the diabetic
mice or of regeneration of the insulin-secreting islets from another
source," says Faustman. "We've found that islet regeneration
was occurring and that cells were growing from both the recipient's
own cells and from the donor cells." An associate professor
of Medicine at Harvard Medical School, Faustman notes that it has
been generally believed that most adult organs cannot regenerate
and that adult stem cells or cellular precursors would not be powerful
enough to reconstitute functioning insulin-secreting islets.
In order to determine whether or not the new islets had developed
from the donated spleen cells, the researchers carried out the same
treatment using spleen cells from healthy male donors to re-educate
the immune cells of female diabetic mice. In those diabetic mice
that achieved long-term normal glucose metabolism, the researchers
found that all of the new functioning islets had significant numbers
of cells with Y chromosomes, indicating they had come from the male
donors. In another experiment, donor spleen cells were marked with
a fluorescent green protein, and again donor cells were found throughout
the newly developed islets.
A separate experiment, however, indicated that islets also could
grow from remaining precursor cells in the diabetic mice and resume
insulin secretion once the autoimmune process had been halted. Such
regrowth from the animal's own cells was slightly slower than regeneration
from donor cells - taking about 120 days - but the eventual regeneration
of islets was just as complete. The result suggests that, given
time, regrowth of islets can occur in animals who have immune system
re-education to eradicate their diabetes but do not receive the
donor islet cell precursors.
The researchers then separated spleen cells into those with a surface
molecule called CD45, which indicates the cell is destined to become
an immune cell, and those without CD45. They injected labeled spleen
cells with or without CD45 - or unseparated cells - into young mice
in which autoimmunity had begun but full-blown diabetes had not
yet developed. After the immune system re-education therapy, all
of the mice maintained normal glucose control, while their untreated
littermates soon became diabetic. However, close examination of
pancreatic tissue from the treated mice revealed markers from the
donor cells only in the islets of those who had received spleen
cells without CD45.
"It's the cells without CD45 that are the precursors for pancreatic
islets. They have a distinct function that has not previously been
identified for the spleen," Faustman says.
Faustman also hopes to investigate whether her diabetes-related
discoveries could be applied to other autoimmune diseases, such
as lupus and Crohn's disease - two disorders believed by many to
be caused by a similar disruption of the same immune process her
team originally identified in diabetes. Her work has largely been
supported by grants from the Iacocca
Foundation, founded by Lee Iacocca in 1984 to fund innovative
approaches to a potential cure for diabetes. "The Iacocca Foundation
has been willing to bet on projects that tackle the hard questions
of autoimmunity," Faustman says. "We wouldn't be where
we are today without their generous support."
"Dr. Faustman's research has significant implications not only
to the future of diabetes treatment, but also to other autoimmune
diseases," says Kathryn Iacocca Hentz, president of the Iacocca
Foundation. "It may someday be possible to apply her technique
in reversing rheumatoid arthritis, multiple sclerosis and lupus."
The MGH research team has also received funding from the National
Institute for Diabetes, Digestive and Kidney Diseases; the Cure
Diabetes Now Foundation; and the American Autoimmune-Related Diseases
Association Foundation. Co-authors of the Science paper are first
author Shohta Kodama, MD, PhD; Willem Kuhtreiber, PhD; Satoshi Fujimura,
PhD, and Elizabeth Dale, all of the MGH Immunobiology Laboratory.
The Iacocca Foundation has been a leader in the battle against diabetes
for the past 20 years and has granted more than $20 million to innovative
and promising research. The Foundation was established by Lee Iacocca
in honor of his late wife, Mary, who died from complications of
type 1 diabetes.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $350 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, the MGH joined
with Brigham and Women's Hospital to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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