The trial, conducted in the US through the international Type 1 Diabetes TrialNet consortium and published in the New England Journal of Medicine, provides the first conclusive evidence that it is possible to target particular types of immune cells to reduce or prevent the onset of type 1 diabetes.

The compound, called rituximab, specifically targets a type of immune cell known as B cells. B cells organize the immune system and are responsible for telling other cells when and where to attack. Previous research has shown that reducing the number of B cells in mice predisposed to type 1 diabetes resulted in the disease being delayed and even prevented. The big question was whether it would also be the case in humans.

Excitingly, it was. Researchers reported that patients given rituximab treatment had a significantly slower disease progression, better blood glucose control and lower insulin requirements compared to the control group.

Some challenges were experienced, however. Patients on the rituximab treatment were given four doses of the drug over a one year period yet most experienced a decline in effect soon after treatment stopped. Some patients also experienced side effects that, though relatively mild, were not desirable for long term treatment.

Researchers will now conduct further trials to look at ways of prolonging the action of the treatment to ensure the autoimmune process that causes type 1 diabetes is safely prevented in the long term.

While work is yet to be done, this research is the first step towards the development of a safe and effective way to prevent the immune attack behind type 1 diabetes — an essential prerequisite for both disease prevention ongoing protection for insulin-producing replaced or regrown through other means.

JDRF-funded researchers Ms Eliana Mariño and Dr Shane Grey have demonstrated the cells of the human immune system can be manipulated to prevent type 1 diabetes.

The body’s immune cells, or white blood cells, include B cells and T cells. B cells make antibodies and present ‘antigens’ to T cells, allowing them to recognise and kill invaders.

Previous research by the authors has showed that groups of B cells migrate to the pancreas and pancreatic lymph nodes and tell T cells to kill the cells that produce insulin.

Working with mice that spontaneously develop type 1 diabetes, the team used a special molecule called BCMA to block a hormone responsible for controlling the survival of B cells, called BAFF. As the B cells were removed using this technique, a special type of T cell (called regulatory T cells) increased and prevented the autoimmune attack on the pancreatic cells.

They found that after this treatment, none of the mice developed type 1 diabetes – a remarkable finding, as other B cell depletion methods have just delayed or reduced disease incidence.

The molecule BCMA is already being used in clinical trials for other autoimmune diseases, such as Sjogren’s Syndrome and Lupus and this result provides support for the development of a human type 1 diabetes trial.

This work was conducted under the auspices of the Diabetes Vaccine Development Centre (DVDC) at the Garvan Institute of Medical Research in Sydney.

Diabetes published online April 29 2009

PhD student Eliana Mariño and Dr Shane Grey, from the Garvan Institute of Medical Research in Sydney, have demonstrated how a particular molecule may be used to prevent type 1 diabetes in the future. Their findings are published online in the international journal Diabetes.

JDRF’s Research Development Manager said this research, part funded by JDRF, is significant. “These results are impressive and they represent a promising step towards a vaccine for type 1 diabetes.”

“Significantly, related compounds have already been approved for clinical trials for other autoimmune diseases such as lupus, so we hope to see clinical trials with humans to prevent type 1 diabetes in around five years time.”

PhD student Eliana Mariño and Dr Shane Grey are pictured here with JDRF Youth Ambassador Brendan Rose.

How it works

White blood cells, the cells of the immune system that defend the body against infectious disease and foreign materials, include B cells and T cells. The B cells make antibodies and present ‘antigens’ to T cells, which help them to recognise, and kill, invaders.

In previously published studies about Type 1 diabetes, Dr Grey’s lab has shown that groups of B cells migrate to the pancreas and pancreatic lymph nodes, presenting specific insulin antigens to T cells. In other words, B cells go to the disease site and tell T cells to kill the cells that produce insulin.

“This study looks at different ways of subduing B cells, and how that affects development of the disease,” said Grey.

Working with mice that are genetically programmed to develop type 1 diabetes (NOD mice), Eliana Mariño found that if she blocked B cells known as BAFF cells, which control cell survival, before the mice developed type 1 diabetes, none of the mice in the study developed the disease.

“This is a remarkable finding, as other B cell depletion methods tested elsewhere have just delayed or reduced disease incidence,” said Eliana.

When B cells were depleted, the regulators of the immune system (a subclass of T cells known as T regulatory cells) rose in numbers.

By removing B cells from the picture for a while, it appears you allow T regulatory cells to function as they should, subduing killer T cells and somehow making them tolerant of the insulin producing cells.

The molecule used by Grey and colleagues to inhibit BAFF is known as BCMA, and is already being used in clinical trials for other autoimmune diseases, such as Sjogren’s Syndrome and Lupus.

Next Steps

The Diabetes Vaccine Development Centre (DVDC), which seeks to develop a vaccine for type 1 diabetes, is funding further research with the compound.

The DVDC is a jointly supported initiative of Australia’s National Health and Medical Research Council and the Juvenile Diabetes Research Foundation International and is administered through the Garvan Institute of Medical Research

TV News

This story was covered by ABC TV. Click on Video to hear YA Brendan Rose and JDRF Research Development Manager Dr Dorota Pawlak discuss this research.

ABOUT GARVAN

The Garvan Institute of Medical Research was founded in 1963. Initially a research department of St Vincent’s Hospital in Sydney, it is now one of Australia’s largest medical research institutions with nearly 500 scientists, students and support staff. Garvan’s main research programs are: Cancer, Diabetes & Obesity, Immunology and Inflammation, Osteoporosis and Bone Biology, and Neuroscience. The Garvan’s mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan’s discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.

Garvan Institute Media enquiries

Alison Heather, Science Communications Manager, Garvan Institute of Medical Research, 0434 071 326

JDRF Media enquiries

Lyndal Howison, Media and PR Executive, Juvenile Diabetes Research Foundation, 0411 110 717