Our lab studies a crucial part of our immune system – immune tolerance checkpoints.
Our research is focused on understanding a critical process for our health: how the immune system distinguishes the normal parts of our body (‘self’) from microbes that invade our body (‘non-self’) or cancer cells that arise in our body (‘altered self’) so that only microbes and cancer cells are targeted by destructive immune reactions. Our research pioneered the discovery that a series of immune tolerance ‘checkpoints’ ensure immune reactions are correctly targeted away from self.
Improving checkpoint inhibitor treatment of cancer
Circumventing immune tolerance checkpoints with ‘checkpoint inhibitor drugs is now a powerful third pillar of cancer treatment. One line of research in the lab is using genomic technologies and computational tools to reveal why immune reactions to destroy cancer cells are better in some people treated with checkpoint inhibitors than others, and why this correlates with the cancer treatment also triggering an autoimmune disease. By learning from patients who are 'exceptional responders’, our research has illuminated a strategy to improve checkpoint inhibitor treatment for cancer generally
HOPE: Identifying the root cause of autoimmune disease
As the hub for a network of interdisciplinary collaborators in the HOPE Research Program, we are revealing how immune tolerance checkpoints break down in the 100 different autoimmune diseases, including rheumatoid arthritis, psoriatic and other autoimmune arthritis, Sjögren’s syndrome, systemic lupus erythematosus, scleroderma, autoimmune anaemia / thrombocytopenia / neutropenia, vasculitis, kidney glomerulonephritis, arteritis, demyelinating neuropathies including myasthenia gravis, multiple sclerosis, myositis, celiac disease, inflammatory bowel disease, thyroiditis and type 1 diabetes.
A key thrust of the HOPE Research Program employs cutting-edge genomic technologies and computational tools, in particular single cell RNA/DNA/protein analysis, to reveal ‘rogue clones of lymphocytes that cause a person’s autoimmune disease. In a growing number of autoimmune diseases, we have identified rogue clones and discovered how they evaded immune tolerance checkpoints: by acquiring somatic mutations in genes that govern the checkpoints. The same mutations also drive the rogue clones responsible for common blood cancers such as chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, Waldenstrom’s macroglobulinemia, monoclonal gammopathy of unknown significance and T cell large granular lymphocytic leukaemia.
The HOPE Research Program is thus revealing that the root cause of some autoimmune diseases is also the benign stage of cancer. This surprising connection opens up strategies to improve the treatment of autoimmune disease and of early-stage cancer with new targeted therapies that are currently being developed for late-stage cancer.
The HOPE Research Program is also revealing how inherited gene differences, epigenetic abnormalities and environmental triggers such as common infections (e.g. hepatitis C virus, Campylobacter jejuni, Epstein-Barr virus) or diet (e.g. gluten) also drive the development of rogue clones, leading to autoimmune disease
COVID-19: Inventing a universal vaccine
Our immune tolerance checkpoint research has discovered how our antibodies normally acquire an extraordinarily narrow specificity for a single molecular target. That process ensures that when we make antibodies against a microbe they don’t also bind and destroy ‘self’. The SARS-CoV-2 virus exploits the narrow specificity of antibodies, enabling the virus to evade our current COVID-19 vaccines and spread the pandemic. The Omicron variant and its BA.4/BA.5 descendants have already caused two additional, global waves of infection and re-infection, simply because most of the virus-blocking antibodies we made were too narrowly targeted against the original Wuhan strain and didn't bind the mutated Omicron strains. Unless we can invent a vaccine that elicits ‘broadly neutralising antibodies effective against all possible SARS-CoV-2 variants, our society will be locked in a perpetual cycle of new waves of SARS-CoV-2 reinfection every year. Those infections, in turn, will cause a massive burden of chronic illnesses, miscarriages and other debilitating disorders. Applying its skills to COVID-19, the collaborative consortium has discovered a way for vaccines to elicit broadly neutralising antibodies against SARS-CoV-2: so broad that they bind just as strongly to the distantly related SARS virus that caused a global outbreak in 2003. A key thrust for the team now is to translate that proof-of-principle discovery into a universal COVID mRNA vaccine that ends the pandemic.