Retraining the immune system may hold key to diabetes prevention
People with Type 1 diabetes could one day see the faulty cells in their pancreas either restored to health or replaced with new ones thanks to new research that could improve the lives of millions of people around Europe.
(The story was first published in Horizon Magazine)
Type 1 diabetes is an autoimmune disease, meaning the body’s defence mechanisms mistakenly attack its own cells and organs. In this case, the immune system attacks insulin-producing beta cells in the pancreas, meaning that the body’s ability to process sugar, in the form of glucose, is damaged.
The abnormal blood sugar levels seen in people with diabetes can lead to serious complications ranging from blindness and kidney failure to stroke and foot amputations.
Today, people with Type 1 diabetes must inject themselves with insulin on a regular basis to avoid falling into a diabetic coma and to minimise their risk of serious long-term complications.
But researchers have been looking at alternative ways to solve the problem and believe beta cells are the key to preventing Type 1 diabetes from developing or getting any worse.
Professor Colin Dayan at the University of Cardiff wants to teach the immune system not to attack these precious beta cells. He is leading the EU-funded EE-ASI project exploring antigen-specific immunotherapy (ASI) which helps the body to recognise its own beta cells and suppresses any attempts by the body to attack them.
ASI works by introducing the part of the proteins that are targeted by the immune system into the body in a manner that does not cause inflammation. This allows the immune system to learn to tolerate the substance and reset its autoimmune response.
It is hoped that this method could be used as a kind of diabetes vaccine that would save insulin-producing beta cells.
‘Some call this a diabetes vaccine because it targets the immune system and protects against disease,’ says Prof. Dayan. ‘In a sense, it’s the opposite – an unvaccine – because instead of using the immune system to destroy an invading virus or bacterium, we want it to tolerate its own beta cells.’
Prof. Dayan believes that such treatment would be a better solution than using immunosuppressive drugs to temper the immune response.
‘The side effects of suppressing the immune system would be too much, particularly as people would need to take these medicines for the rest of their lives,’ he explained.
However, the challenge for Prof. Dayan’s team is to deliver this vaccine to where it is needed – the lymph nodes, especially those in the pancreas – without inadvertently activating the immune system. To do this, they are using gold nanoparticles – tiny specs of gold which are increasingly used as modern-day drug delivery couriers.
‘These are 5 nanometres in size – about as small as you can get – and ideal for our purposes,’ said Prof. Dayan. ‘Gold nanoparticles are inert. They calm the immune system rather than trigger a reaction and, because of their size, cells like to take them up.’
The gold nanoparticles, which can be injected just under the skin using microneedles, are produced by one of the small companies that works on the EE-ASI project. The group is now preparing for a small clinical trial of the diabetes vaccine which, ultimately, could be given to people at high risk of developing the disease.
Type 1 diabetes begins to damage beta cells from a very early age, possibly even in the first year of life, and the disease is typically diagnosed at 12 years of age. Intervening soon after diagnosis or even before serious damage has been done could stop or slow disease progression.
For people who have had Type 1 diabetes for several years, however, it is too late to preserve beta cells. But there is still reason to hope: stem cell therapies could replace the damaged insulin-producing cells, essentially curing diabetes.
The challenge is to understand how stem cells can be turned into functioning beta cells and then to transplant these into patients.
To do this, Professor Henrik Semb at the Danish Stem Cell Center at the University of Copenhagen is working with pluripotent stem cells – a kind of immature cell which, in the right environment, can become any other type of body cell, a process known as differentiation.
The EU-funded HumEn project, led by Professor Semb, has been unpicking the mechanisms that lead pluripotent stem cells to become pancreatic beta cells and how to scale up this process. ‘For the up-scaling we are focusing on two stages of pancreatic differentiation known as definitive endoderm and pancreatic endoderm progenitors,’ said Prof. Semb.
The pancreatic endoderm progenitors could hold particular promise as these are the cells that determine the final size of the pancreas during embryonic development. The researchers are studying how to manipulate the expansion of these cells in the lab by exposing them to growth-promoting chemicals as well as physical forces such as pulling and stretching.
‘We are now able to make insulin-producing cells that work like normal beta cells in that they respond to changes in the glucose levels,’ Prof. Semb said. ‘The next step is to uncover what the signals are that regulate the expansion of the endodermal progenitors.’
If this can be achieved, the next task will be to figure out how to safely and reliably produce enough cells to develop a cell therapy product that helps patients. The consortium is also working with immunologists to understand how these cells might be introduced into the bodies of diabetic patients without being rejected.
‘I am very hopeful that in a couple of years we could perform the first trial,’ said Prof. Semb.