Most autoimmune diseases are easy to diagnose but hard to treat – but a new study by the Garvan Institute of Medical Research and UNSW Sydney has revealed a path for better treatment of autoimmune diseases.

The research published today in Science suggests that our immune cells’ unique ‘fingerprints’ can be used to rapidly identify autoimmune disease treatments. The study is the largest study to date to link disease-causing genes to specific types of immune cells.

“Because of our immune system’s complexity, and how vastly it varies between individuals, we don’t currently have a good understanding of why a treatment works well in some people but not in others,” says the joint lead author Professor Joseph Powell, Director of Cellular Science at the Garvan Institute of Medical Research and Deputy Director of the UNSW Cellular Genomics Futures Institute.

The new discovery, led by the Garvan Institute of Medical Research, could help individuals find tailored treatments that work for them and guide the development of new drugs. It also helps us understand why some treatments work well for some patients but not others.

A million cells of complexity

The study looked at genes in individual immune cells on a large scale. It analysed the genomic profile of more than one million individual immune cells from around 1000 healthy individuals, exploring 14 different types of immune cells.

“We were able to do this using single-cell sequencing, a new technology that allows us to detect subtle changes in individual cells,” says Prof. Powell.

The study links specific genes and immune cell types to the disease of an individual, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes and Crohn’s disease. This means a person’s unique genetic profile could be used to deliver treatments tailored to their immune system.

This individual approach paints a clearer picture of what happens in immune cells than previous studies which analysed combined cells in a blood sample.

“The problems with bulk RNA analysis is that we only observe an averaged signal. But there is vast variation in cell functions and cell types that allow the body to defend against attack,” says Dr Seyhan Yazar, co-first author of the study and Senior Research Officer at Garvan Institute of Medical Research. “Average analysis doesn’t reflect what happens in the full variety of immune cells.”

Our bodies’ immune systems are designed to fight external threats, but autoimmune diseases occur when our immune systems take aim at our own healthy cells. They affect about one in 12 Australians, are incurable and require lifelong treatments to minimise the damage.

“Most rare genetic diseases are like a major car accident in the body – they are generally easy to identify and locate where they occur in the genome. But immune diseases are often more like traffic congestion, where genetic changes that hold up traffic are harder to specifically pinpoint. This study has helped us identify the trouble spots,” says Professor Alex Hewitt, joint lead author and clinician-researcher at the University of Tasmania’s Menzies Institute for Medical Research.

Often, patients will trial many different treatments before finding one that works for them.

“Some medications may be very effective in only 15 per cent of patients, so are not recommended as a first-line treatment,” says Dr Yazar. “We now have a way to link treatment response back to an individual’s immune genetics – and to potentially screen for that 15 per cent of patients before a clinician even administers a treatment.”

Matching treatments and patients

The researchers say the findings could help lower the risks associated with developing new treatments.

“Understanding which cell types are relevant for a particular disease is key for developing new drugs,” says Dr José Alquicira-Hernández, co-first author and researcher at the Garvan Institute.

“Pharmaceutical companies may have hundreds of targets and have to make decisions about which they will take forward to Phase I clinical trials, knowing that 90 per cent of potential drug candidates fail during clinical development.”

“The greatest insight from this work will be identification of therapeutic targets and defining subpopulations of immune disease, which can then refine clinical trials to assess drug effectiveness,” Prof. Hewitt says.

A trial is now underway in Sydney with Crohn’s disease patients to identify which treatments work for specific patients.

“We are working on a study of Crohn’s disease in collaboration with St George Hospital that will determine how a patient’s immune genotype affects their response to different treatments and are looking to establish new trials in a range of autoimmune diseases,” says Prof. Powell.

“It is a significant milestone of Garvan’s pioneering OneK1K study aimed at showing how genetics contribute to the risk of immune disease at a cellular level.”

The research was supported by National Health and Medical Research Council Research Fellowship, Practitioner Fellowship, Career Development Fellowship and Investigator Fellowship; The Alex Gadomski Fellowship, funded by Maddie Riewoldt’s Vision. Additional grant support was provided by the National Health and Medical Research Council, the Australian Research Council and the Royal Hobart Hospital Research Foundation.

Other authors of the paper are from: Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research; Institute for Molecular Bioscience, University of Queensland; Royal Hobart Hospital; University of California; Monash University; Wicking Dementia Research and Education Centre, University of Tasmania; Institute of Computational Health Sciences, University of California; and Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub.