Published 7 April 2016 

By Dr Fiona McMillan

New research from the University of Queensland Diamantina Institute reveals that it is possible to specifically turn off certain immune memory cells that are harmful in Type 1 Diabetes (T1D). Not only could this limit the progression of T1D but it could substantially improve islet transplant outcomes, and thus facilitate reversal of the disease.

The Islets of Langerhans are small cell clusters in the pancreas that play a crucial role in the regulation of blood sugar. This is because they contain beta-cells, which are the only cells in the body capable of making the hormone insulin. Insulin, in turn, is essential for moving glucose into the body’s cells where it can then act as a source of energy. To use a common analogy, insulin is like a key that opens up a doorway on a cell. Without it, the glucose can’t get in.

In T1D, a person’s own immune cells mistake their beta-cells for foreign pathogens and destroy the beta cells in the pancreatic islets of Langerhans. Whereas a healthy pancreas may contain around one million islets, by the time symptoms begin to show, a person with T1D may only have around 10% of these left. As the disease progresses this drops further leaving these people with no way to produce their own insulin. Consequently, they require life-long insulin management and can suffer an array of debilitating complications.

Given that the loss of beta-cells leads to the major health problems associated with T1D, then re-establishing those cell populations is the ideal treatment. New stem cell technologies are enabling scientists to grow a patient’s own pancreatic islets. This approach allows large quantities to be grown and avoids the problem of transplant rejection that can occur when islets come from another donor. However, the autoimmune reaction — that mistaken attack of beta-cells that caused the T1D in the first place — remains a problem. No matter where the new beta-cells come from, the immune reaction restarts because it targets proteins common to all beta-cells. The immune system always remembers because a type of cell, called a memory T-cell, ensures that it does.

The UQDI research team, led by Associate Professor Ray Steptoe, have now found a way to give the immune system a very specific and enduring bout of amnesia. He explains that if any islet transplant is to work long term, the memory T-cells that target beta-cells must be destroyed or rendered ineffective. It would have to be incredibly precise, of course. Turning off all memory T cells would be dangerous; we need them to fight infections.

As a proof of concept in mice, Steptoe and his colleagues developed a population of memory T cells that target one particular protein. They then showed that any beta-cell with this protein on its surface was quickly recognised and destroyed by the immune system. That was part one. The researchers then turned their attention to another group of immune cells, called dendritic cells. Dendritic cells are like teachers: they tell other immune cells what to attack and what to ignore. The researchers gave the mice some dendritic cells that did something counterintuitive: instead of telling the memory T-cells to calm down and ignore the target protein, these new dendritic cells made the memory T-cells very excited about hunting down that protein. The trick was that the memory T-cells became so overstimulated that they became exhausted and unresponsive. In fact, many of them simply died. It was also very specific: only the memory T-cells that targeted that particular protein on the beta-cells were affected, all the other memory T-cells were fine.

Steptoe wanted to know if this would work in a mouse model of diabetes. Would it really help stabilise the regulation of glucose? Using the approach described above, the researchers enabled mice to grow dendritic cells that specifically over-excited and wiped out problematic memory T cells in diabetic mice. The mice then received a graft of fresh islets. As a result, glucose control was restored.

“Almost all of the grafts survive when given the treatment compared to controls,” says Steptoe.
In effect, the mice no longer had diabetes.

This work was done using a test protein as a target. The next step is to see if this works for all the proteins on beta-cells that usually trigger immune responses in T1D. Steptoe’s team are progressing to studies that look at these diabetes ‘antigens’ and how they can use this approach in humans. This work is likely to influence research, not only on T1D, but also on a wide range of autoimmune conditions where memory T cells play a role in persistent, unwanted immune responses.

 

MEDIA: Kate Templeman on 0409 916 801 or k.templeman@uq.edu.au

 

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