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This press release is an announcement submitted by Massachusetts General

Hospital, and was not written by Diabetes Health.

In experiments using blood cells from human patients with diabetes and other

autoimmune disorders, Massachusetts General Hospital (MGH) researchers have

confirmed the mechanism behind a potential new therapy for type 1 diabetes.

A team led by Faustman, MD, PhD, director of the MGH Immunobiology

Laboratory, showed that blocking a metabolic pathway regulating the immune

system specifically eliminated immune cells that react against a patient's

own

tissues.

Faustman and her colleagues previously discovered a technique that reversed

type 1 disease in a mouse model. The current study, which will appear in

the

Proceedings of the National Academy of Sciences and has been released

online, is the first demonstration of this strategy in human cells and

supports the

viability of a clinical trial that is currently underway.

" Our studies in mice showed that we could selectively kill the defective

autoimmune cells that were destroying insulin-producing islets, " says

Faustman.

" These results show that the same selective destruction can occur in humans

cells and connects what we saw in our animal studies with the protocol we

are pursuing in our Phase I clinical trial. "

Type 1 diabetes and other autoimmune diseases are caused when the body's

immune cells mistakenly attack the body's own cells. In several studies over

the

past decade, Faustman's team showed that triggering the expression of the

immune-system modulator tumor necrosis factor (TNF) in diabetic mice led to

the

death of the T cells responsible for destroying insulin-producing pancreatic

islets. After receiving this treatment, the animals were able to regenerate

healthy islet cells that produced normal levels of insulin, effectively

curing the animals' diabetes.

The current study used T cells from more than 1,000 patients with type 1,

other autoimmune disorders, and healthy controls. First the researchers

found

that treatment with TNF killed CD8 T cells, the immune system's " killer "

cells, from patients with diabetes, but not CD4 " helper " T cells. TNF

treatment

also induced the death of CD8 T cells from other autoimmune disease

patients, but had no negative effect on cells from healthy controls.

Because TNF interacts with immune cells through two different

receptors-TNFR1 and TNFR2, which activate different signaling pathways-the

researchers next

tested several TNF agonists, substances that mimic the molecule's actions.

One of those TNF agonists acts through TNFR1, which is expressed on all T

cells,

and three act through TNFR2, only found on subpopulations of T cells. While

neither the TNFR1 agonist nor two of the three substances that activate the

TNFR2 pathway had any significant effects, a third TNFR2 agonist induced

cell death in particular CD8 cells from patients with diabetes and other

autoimmune

disorders. As with TNF treatment, no cell death occurred in cells from

healthy participants.

Further experiments with blood samples from several diabetic patients

revealed that the population of CD8 T cells responsible for the autoimmune

destruction

of pancreatic islets consistently died after treatment with the TNFR2

agonist, while similar cells from a non-diabetic proliferated. However, CD8

cells

from diabetic participants that were targeted against two common viruses

were not killed by exposure to the TNFR2 agonist, confirming that the

protocol

only leads to the death of T cells responsible for an autoimmune reaction.

The clinical trial, based on Faustman's earlier studies, is testing whether

use of bacillus Calmette-Guerin (BCG), a generic drug that temporarily

elevates

TNF levels, will reduce autoimmune T cells in patients with type 1 diabetes.

The current Phase 1 trial, which has been approved by the FDA and is

directed

by M. , MD, director of the MGH Diabetes Center, focuses on

determining the optimal dose and timing of BCG administration. More

information

on the 18-month trial, which began in March, is available at

http://www.faustmanlab.org/.

Faustman is an associate professor of Medicine at Harvard Medical School.

The lead author of the PNAS study is Liqin Ban, and additional co-authors

are

Jack Zhang PhD, Limei Wang, PhD, Willem Kuhtreiber, PhD, and Berger,

PhD all of the MGH Immunobiology Department.

Source: Massachusetts General Hospital