Read about our asthma and allergy research.
The novel thinking behind the asthma vaccine has its genesis in a discussion between Associate Professor Ian Hermans and Professor Franca Ronchese, puzzling over results from their cancer vaccine research.
The pair had noticed that the dendritic cell-based vaccines were very effective at starting an immune reaction, but almost not active at all once the reaction was established. Perhaps the immune reaction was blocking the activity of the dendritic cells?
Later, Professor Ronchese realised that the observation could be useful in another context. It was a turning point. I wondered if this mechanism could be harnessed for asthma, where the dendritic cells are the ones that start the unwanted immune response, which leads to inflammation and the symptoms of asthma, she explains.
The asthma vaccine, which is a chemically linked combination of adjuvant and antigen, was made by the Malaghan Institutes chemistry collaborators at the Ferrier Research Institute. Linking the two components ensures they reach the target cells together and create a powerful, highly specific immune response.
The mice were sensitised to an egg-based allergen, immunised with the vaccine, then given the allergen to inhale. We saw no inflammation in the immunised mice it was a very exciting result.
What we think is happening is that we are directing the killer T cells to go and block the dendritic cells, so they stop sending out the wrong messages. Its like taking out the generals of the enemys army in order to overpower it.
Following on from research published in Nature Chemical Biology in 2014 describing a successful trial of a vaccine targeting asthma, Professor Franca Ronchese’s team have fully described the vaccine’s mode of action.
“Although we suspected what was going on, we didn’t know for sure. This research used three different methods to prove that our initial results showing a suppression of the allergic response were correct,” she says.
The research demonstrated that asthma-causing dendritic cells are attacked by cytotoxic T-lymphocytes (CTL, a type of immune cell) that are produced by the immune system after exposure to the vaccine. Using a mouse model, treatment with CTL caused the dendritic cells to express suicide molecules (that result in their death) and the number of dendritic cells also declined.
In addition, observations of cells in the lungs found CTL in close proximity to the dendritic cells. “Understanding how this vaccine works is very important – you cannot make a drug better until you understand exactly how it works. We now know that the vaccine is going to the right cells and why it induces such a good immune response.”
When the complete human genome was first sequenced in 2003, it took more than a decade, required huge machines and cost billions of dollars. Next generation sequencers were a step smaller, faster and cheaper, and were centralised because of the cost.
The new sequencer being trialled by Professor Mike Berridge, Dr James Baty and bioinformaticist David Eccles is about the size of a muesli bar and can sequence DNA on site in hours.
Developed by Oxford Nanopore Technologies, the miniature sequencer connects to a laptop via a USB cable. The genetic sequences are read off as the DNA in a sample is sucked through tiny pores in the MinION device.
DNA sample preparation is also radically simplified, which opens the way for the technology to be applied to many other medical, health and biological problems.
The Malaghan Institute is one of about 500 laboratories worldwide that are currently trialling a prototype sequencer before a final version is commercialised.
“It's a very impressive device that changes almost everything about how sequencing is done. We don’t have to send samples of DNA away to be sequenced, but can do it here, in real time,” says Professor Berridge. “It’s not designed for large-scale whole genome sequencing but its size, speed and convenience is revolutionary for the work we are doing.”
Listen to the podcast (titled Speedy sequencing), aired on RNZ National on 13 September 2014.
Research headed by Professor Franca Ronchese and now published in the Journal of Immunology, concludes that allergies change the properties of a certain type of dendritic cell found in the skin. It’s the dendritic cell that then tells the immune system how to respond.
“This study is significant because, while we know a lot about the symptoms of allergies, comparatively little is understood about the detail of what starts an allergic response,” says Dr Lisa Connor, a researcher in the immune cell biology programme.
“This research is exciting news for the Malaghan Institute. Years of research around the world demonstrate that dendritic cells play a key role in the immune system owing to their ability to control both immune tolerance and immunity. The ultimate goal our research is to use these new discoveries to develop ways of generating therapeutic immunotherapies against allergies. In essence, we are seeking an “off switch” for allergic responses.”
Allergies are very common and affect about one in three New Zealanders at some time in their lives. The incidence of allergic diseases has increased significantly over the last two and a half decades, and is regarded to be a global epidemic. It is now recognised that there is a progression of disease; children with dermatitis are more likely to develop food allergies, followed by respiratory allergies such as asthma and hay fever. This progression is called the ‘allergic march’. It is thought that by inhibiting the early development of allergic diseases the likelihood of more severe forms occurring later in life should decrease.
While the progress reported in the paper fills a knowledge gap, many challenges remain. For many diseases, including allergies, key pieces of the immune pathways remain unclear.The research is focused on the skin, but next steps will include looking at dendritic cells in the gut and lungs as well as developing a detailed inventory of their characteristics and behaviour.
This study was supported by the Health Research Council of New Zealand.