Immune Cell Entry Into the Pancreatic Islets Key to Understanding Type 1 Diabetes Origins

Immune Cell Entry Into the Pancreatic Islets Key to Understanding Type 1
Diabetes Origins

St. Jude Children's Research Hospital study results suggest new approaches for
preventing disease

MEMPHIS, Tenn., Oct. 8 /PRNewswire-USNewswire/ -- St. Jude Children's Research
Hospital investigators have discovered how destructive immune cells gain
access to insulin-producing cells and help cause diabetes.

The finding points to possible new strategies to halt or prevent type I
diabetes.

Working in mice, researchers demonstrated that to enter key areas of the
pancreas known as the islets of Langerhans, immune cells known as T cells must
recognize a marker on the surface of insulin-producing cells housed there. T
cells play a key role in regulating immune response. Once inside the islets, T
cells trigger the inflammation that can lead to destruction of the
insulin-producing beta cells. The result is type I diabetes.

The report answers a fundamental question about the role of T cell entry and
accumulation in the islets in development of type I disease, a disease that
affects as many as 3 million Americans. The research appears in the October 16
edition of the journal Immunity. Dario Vignali, Ph.D., is the paper's senior
author and vice chair of the St. Jude Immunology department.

The St. Jude results contradict a widely held theory that only a small
percentage of T cells that infiltrate the islets were actively involved in
causing type I diabetes. The old scenario held that most of the T cells found
in the islets were recruited to the site by a small number of specialized T
cells. Those recruited or bystander T cells were thought to play no role in
causing diabetes. Furthermore, it was thought that any T cell could gain
access to the islets.

"The new research argues that every T cell in the islet is important. What
these T cells recognize that allowed them to gain access to the islets may
provide us with clues as to what might be needed to prevent diabetes," Vignali
said. "Understanding the molecular differences between the T cells in the
islets and the T cells in the periphery might also start to tell us a lot
about what it takes to make a T cell attack the beta cells and cause
diabetes."

Without insulin to turn food into fuel for cells, patients develop type I
diabetes and are left dependent on insulin injections, an insulin pump or in
rare cases a pancreas transplant. Unlike the more common form of the disease,
known as type II diabetes, type I diabetes usually affects children and is
sometimes called juvenile diabetes. About 15,000 new cases are diagnosed
annually in the United States. Even with treatment, patients with type I
diabetes are at risk for blindness, kidney failure and other complications.

"This paper also presents a new clinical intervention strategy--blocking T
cells from even getting into the islet cells in the first place," Vignali
added.

If any T cell could enter the islets, then it would be less likely that there
were any "special rules" for entering islets and thus nothing unique about
entry into the islets that might be targeted by treatment, he explained.

Understanding how T cell access to islets is controlled also raises hopes for
developing a therapy to re-educate the immune system to tolerate rather than
attack the beta cells. The St. Jude research points to a new route into islet
cells.

For this study, scientists used a technique Vignali's laboratory developed in
2006. The technique allows researchers to quickly modify T cell production in
mice. Normally mice make millions of T cells that can recognize many different
cells and microorganisms. Each T cell carries on its surface a receptor that
recognizes and binds to just one specific antigen, or marker, on the surface
of the T cell's intended target.

The modification technique allowed researchers to create strains of mice with
only two types of T cells, each with different receptors. One population
carried a receptor that recognized the insulin-producing beta cells and could
cause diabetes. The other group was programmed to recognize a different
antigen. Researchers reported they could not induce the latter group of T
cells to enter the islets.

Then investigators created and tracked T cells with three types of
receptors--receptors from T cells with a proven ability to enter islet cells
and cause diabetes, those able to enter islets and cause inflammation, but not
diabetes, and a third group of receptors with no connection to type 1 diabetes
or islet cells. The scientists reported that none of the T cells, even those
with a demonstrated ability to cause diabetes in mice, could induce bystander
T cells to enter the islet cells.

Finally, investigators tracked T cells carrying receptors from mice that
naturally developed type I diabetes. They created mice with 17 new T cell
receptors, five from the spleen of diabetic mice and 12 from T cells isolated
in the islets of those diabetic mice. If the islets control T cells entry,
then islets in the new mouse strains would be infiltrated by T cells with
islet-derived, but not spleen-derived, receptors.

That is what happened. "About 70 percent of the receptors that came from the
islets could mediate T cell migration back into the islets, while none of the
receptors that came from the spleen could do likewise," Vignali said. The
islet-derived receptors were also linked to rapid development of diabetes,
with one-third causing diabetes during the 10-week study.

Vignali said it is unclear if the findings will hold true for other autoimmune
diseases, such as rheumatoid arthritis or Crohn's disease. The authors noted
that the structure, location and other factors might make the islet cells
unique.

Greig Lennon, Maria Bettini and Amanda Burton, of St. Jude, shared first
authorship on this study. The other authors were Erica Vincent and Paula
Arnold of St. Jude, and Pere Santamaria of the University of Calgary, Alberta,
Canada.

The work was supported in part by the Juvenile Diabetes Research Foundation
International, the National Institutes of Health and ALSAC.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its
pioneering work in finding cures and saving children with cancer and other
catastrophic diseases. Founded by late entertainer Danny Thomas and based in
Memphis, Tenn., St. Jude freely shares its discoveries with scientific and
medical communities around the world. No family ever pays for treatments not
covered by insurance, and families without insurance are never asked to pay.
St. Jude is financially supported by ALSAC, its fundraising organization. For
more information, please visit www.stjude.org.

SOURCE St. Jude Children's Research Hospital

Carrie Strehlau, +1-901-595-2295, carrie.strehlau@stjude.org or Summer
Freeman, +1-901-595-3061, summer.freeman@stjude.org, both of St. Jude
Children's Research Hospital