Potential diabetes treatment selectively kills autoimmune cells from human patients

Aug 25, 2008

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 Denise 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 connect 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 an individual'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 diabetes, 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 diabetic patients 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.

Since 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 David M. Nathan, 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 www.faustmanlab.org/ and at www.massgeneral.org/news/relea… /031308faustman.html .

Source: Massachusetts General Hospital

Explore further: Research milestone in CCHF virus could help identify new treatments

add to favorites email to friend print save as pdf

Related Stories

NASA sees Odile soaking Mexico and southwestern US

21 minutes ago

Tropical Storm Odile continues to spread moisture and generate strong thunderstorms with heavy rainfall over northern Mexico's mainland and the Baja California as well as the southwestern U.S. NASA's Tropical ...

NASA sees Tropical Storm Polo intensifying

22 minutes ago

Tropical storm warnings now issued for a portion of the Southwestern coast of Mexico as Polo continues to strengthen. Infrared imagery from NASA's Aqua satellite showed powerful thunderstorms around the center ...

Chemists modify antibiotic to vanquish resistant bacteria

39 minutes ago

Scientists at The Scripps Research Institute (TSRI) have devised a new antibiotic based on vancomycin that is powerfully effective against vancomycin-resistant strains of MRSA and other disease-causing bacteria.

NASA's Maven spacecraft reaches Mars this weekend

52 minutes ago

Mars, get ready for another visitor or two. This weekend, NASA's Maven spacecraft will reach the red planet following a 10-month journey spanning 442 million miles (711 million kilometers).

Recommended for you

A better way to track emerging cell therapies using MRIs

1 hour ago

Cellular therapeutics – using intact cells to treat and cure disease – is a hugely promising new approach in medicine but it is hindered by the inability of doctors and scientists to effectively track the movements, destination ...

New biomedical implants accelerate bone healing

8 hours ago

A major success in developing new biomedical implants with the ability to accelerate bone healing has been reported by a group of scientists from the Department of Restorative Dentistry, University of Malaya. ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

tkjtkj
not rated yet Aug 26, 2008
THis is wonderful and important
stuff, indeed!
At same time , such a statement
as:
"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" are
'over-reaching'! .. "consisten
with" , yes, but 'two cases do
not a confirmation make' !!