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[IP] Tolerance to Donor Tissue in Pancreatic Islet Cell breakthrough

UAB Achieves 'Tolerance' to Donor Tissue in Pancreatic Islet Cell Breakthrough
May 24, 2001

Transplant immunologist Judith M. Thomas, PhD, professor of surgery, and
colleagues at UAB and the National Institutes of Health report in the June
issue of Diabetes success in a longtime goal of transplantation - induction of
tolerance to transplanted tissue without long-tern use of immunosuppressive

In rhesus monkeys, researchers employed carefully targeted immunosuppressive
drugs to briefly reconfigure an immune system likened to that of a newborn
baby. During this immunological window of opportunity, foreign islet cells
were transplanted. After a 14-day period, the drugs were withdrawn, allowing
the immune system to return to normal.

The process of introduction and acceptance of foreign tissue is known as
"operational tolerance" ? long hailed as a "Holy Grail" of transplantation.
Dr. Thomas and colleagues transplanted pancreatic islet cells to reverse
insulin-dependent diabetes in seven rhesus monkeys. One animal rejected his
islet graft, and six have lived for periods up to 18 months without any
immunosuppressive drugs or any need for insulin therapy.

"This study provides the first series showing in multiple recipients that
induction of operational tolerance can protect mismatched non-human primate
islets from rejection as well as from loss of long-term function," says Dr.

"This approach has the potential to make islet transplants a preferential
treatment for juvenile diabetes and prevent the disastrous secondary
complications of diabetes," she says. Dr. Thomas notes that these monkeys were
all juvenile and, probably because they were cured of their diabetes and
simultaneously off all suppressive drugs, all successful islet recipients grew
normally to adulthood, which is a critical goal of juvenile diabetes
treatment. In contrast, primate juvenile diabetics without islet transplant
did not grow normally. The slow growth and other complications the animals
developed were like those of children with diabetes.

For the past 25 years, Dr. Thomas and her research group have sought a way to
trick recipients of organ transplants into accepting unmatched organs without
the need for life-long maintenance on drugs to suppress the immune system.

Prior to the study reported today, the group performed islet transplants to
improve the lives of three adult monkeys suffering from naturally occurring
diabetes. Their diabetes was reversed and tolerance induced in all three of
the animals. One lived for nearly 2 years.

Last year, Canadian doctors reported that transplants of human islet cells
from donor organs had reversed diabetes in a series of human patients, but the
patients are still required to take powerful anti-rejection medication for the
rest of their lives.

"Our current report may open the way for trials of human islet cell transplant
studies with tolerance induction. This suggests that the goal of early islet
transplantation for juvenile diabetes before development of secondary
complications and without infections or maintenance immunosuppressive therapy
may be close at hand with the use of operational tolerance protocols," she

Operational tolerance was achieved at UAB by giving a short treatment with
three drugs to the diabetic recipients beginning on the day of

One drug was a modified, diphtheria-based, CD3 immunotoxin (IT) that
transiently depletes the recipient's T cells from the spleen and lymph nodes
and therefore temporarily eliminates the body's immune response to the donor
tissue. The UAB group reported that the T-cell deficiency was short-term, so
that "T-cell dependent responses in long-term survivors recovered to normal
with no evidence of increased susceptibility to infection." The operationally
tolerant animals reacted normally to subsequent immunization against bacterial
and viral antigens.

The second drug, 15-deoxyspergualin (DSG), arrests production of cytokines
that trigger inflammation and worsen rejection. DSG also suppresses the
maturation of the recipient's dendritic cells, which normally sense foreign
tissues and pass this information to the T cells to reject of transplanted
organs. The third drug was methylprednisolone.

"The combined treatment appears to mask the immune perception of the presence
of a foreign graft so rejection does not occur later, when the immune system
returns to normal," she says. "In effect, it seems that we have reset the
immune system temporarily to that of a newborn baby," Dr. Thomas explains.
"The T-cell immune system is not mature enough to reject the mismatched tissue
for a window of time that allows the islets to 'heal in' and take up residence
after infusion into the liver. The T cells then recover but do not make a
rejection response to the transplanted islets."

Dr. Thomas refers to the system as STEALTH, an acronym for the scientific
mechanism chosen to reflect the ability of the tolerance system to permit the
islet grafts to escape detection by the immune "radar" system.

The transplant immunologist says the maintenance of a functional mass of
transplanted islet cells is crucial to long-term survival without insulin
treatment. "Human pancreas islet cell transplant patients have required two or
even three additional infusions of islet cells, presumably due to loss of
islet mass. Avoiding acute rejection in our series of animals by use of IT and
DSG is probably a major factor in maintaining islet mass and function.

Co-authors of the paper are Juan L. Contreras, MD, Cheryl A. Smyth, Andrew
Lobashevsky, MD, Stacie Jenkins, William J. Hubbard, PhD, Devin E. Eckhoff,
MD, and Francis T. Thomas, MD, all of UAB, and Scott Stavrou and David M.
Neville, Jr., MD, of the National Institute of Mental Health Laboratory of
Molecular Biology.

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