Research supported by the ADTB

There are close to 1700 lives saved by solid organ transplant (SOT) in Australia each year. Infection and immunological complications represent the major determinants of morbidity and mortality and also drive transplant-associated costs so there is an economic as well as clinical imperative for investigating novel approaches to predicting and treating these complications despite existing strategies. Specific bacterial microbiome signatures have been associated with risk of infections and immunological complications after transplant in previous studies. Risk for acute cellular rejection and blood stream infection after liver transplant have both been correlated with microbiome diversity in small single centre cohorts. But understanding of the mechanisms underlying interactions between bacterial and non-bacterial microbial complements, infectious risk and graft survival is currently limited. Definition of these components in well-defined transplant cohorts is essential to capitalise on any opportunity they may present for translation into targets of novel diagnostics and therapeutics.

The immune system can be activated by a range of foreign stimuli such as viruses, prescribed drugs, donor tissue grafts or even self-antigens. These stimuli are presented to the immune system in the form of small protein fragments, called peptides, by specialised molecules on the surface of cells known as human leukocyte antigens (HLA). A specific set of immune cells, called T cells, recognise different peptide/HLA complexes that can trigger either protective (e.g. anti-viral, anti-cancer) or undesirable (e.g. anti-graft, autoimmune, allergy) immune responses. This project seeks to identify peptides from a range of human tissues to determine their involvement in different human diseases.

T cells protect us against infection and cancer, yet dysfunctional T cells cause autoimmune disease. Our knowledge of human T cells largely comes from research using blood and information on how T cells work in solid organs like the gut and lung is scarce. This project aims to decipher how T cells function in various organs in health and disease. The expected outcomes are to gain new knowledge so that we can design new treatments for infection, cancer, and autoimmune disease.

The immune system is a potent weapon for protection against pathogens, including viruses like influenza. T-cells have a central role as their receptors monitor the body for threats. The thymus educates T-cell receptors to discriminate between healthy and infected cells. Receptor diversity and T-cell strength change throughout human life. This project aims to unravel how T-cells gain and lose optimal receptors and strength by understanding how the thymus educates receptors throughout human life. The project is essential for understanding how optimal T-cell immunity is formed, critical if we wish to improve healthy aging and protect against viral infections like influenza.

Heart disease is the leading cause of death in the world. While the causes of cardiovascular disease are typically multi-factorial (diet, genetics, age etc), there is a growing realization that cells of the immune system are active participants in maintaining cardiac homeostasis (i.e. a healthy heart) and conversely, damaging the heart during periods of disease. In this project we will explore this role, characterizing the immune cells that reside within the human heart and determine how these populations act.

Chronic respiratory diseases pose a major public health problem, accounting for 7% of death worldwide (WHO, 2019). We aim to understand the effect of environmental insults on the development of lung disease. Through the analyzing of human lung cells after exposure to cigarette smoke or infections, we aim to better understand the pathology of lung diseases, including COVID19, COPD and lung cancer. The outcomes of this project will be to identify novel therapeutic approaches to prevent or reduce the risk of developing chronic respiratory diseases.

For our bodies to fight off infections or cancer, complex interactions need to take place between white blood cells. Some cells directly capture and destroy bugs, termed phagocytosis, and some capture present foreign matter to other cells, called 'antigen presentation', processes which trigger immune responses. This occurs in all the tissues of our body, however there is much unknown in humans due to the difficulty in obtaining tissue samples. Using human organ donor samples provided by the ADTB, we will measure these cells’ activity in blood and multiple lymphoid, visceral and barrier tissues. We will also generate organoids to study the generation and function of protective immune responses (T cells) in tissues following antigen presentation. The insights gained in this area will lead to new treatments for diverse diseases.

The lymphoid tissues (including the spleen and lymph nodes) are critical for the body to mount immune responses to fight off diseases. These tissues are constructed by stromal cells that are presumed to serve multiple important functions. We aim to determine the role of the lymphoid tissue stromal cells on the functions of these tissues. This is important to identify new targets for the development of novel therapies that can halt the spread of diseases including cancer.

Healthy immune responses help fight infection and cancer, while destructive immune responses lead to autoimmune disease. Immune responses occur in diverse tissue sites like the lung, liver and gut, however, our understanding of human immunology is largely derived from the sampling of blood. Using human organ donor samples provided by the Australian Donation and Transplantation Biobank (ADTB), we will characterise immune responses with a focus on MR1-reactive T cells, a specialised set of small metabolite reactive T cells, in blood and multiple lymphoid, visceral and barrier tissues. A greater understanding in this area will lead to new treatments for infections, cancer and autoimmune diseases.

As disease burdens rise and health systems are overwhelmed globally, the urge to find new treatment strategies becomes imperative. Human gamma-delta T cells are essential components of the immune system, highly represented in solid tissues and at mucosal barriers. However, they remain poorly understood. These cells are thought to play a critical role in the immune system’s ability to monitor tissues and organs for disease and damage. Our research will provide a comprehensive understanding of gamma-delta T cells’ structure and function, endeavouring to translate this research clinically. The aim is to limit the impact of diseases including infection and cancer.

Organoids are mini replicas of organs established in a dish from fresh tissue samples. They retain key characteristics and functions of their tissue of origin and are thus infected by pathogens in the same way as humans. During the COVID-19 pandemic, human organoids were also shown to preserve genome fidelity of the pathogen. Studies with authentic infection of human organoids translated directly to infection of humans. Here we will establish organoid models from the main human organs that harbour infection – respiratory tract, gut and liver – in readiness for the next pandemic, irrespective of target organ.

Although immune-cell locations and functions have been mapped in mice, translating this knowledge to humans is a challenge due to difficulty accessing human tissue. We will provide Doherty researchers much-needed human tissue to address fundamental questions in all aspects of immunity. This information will be used to prevent, treat and cure infections by developing new vaccines and immunotherapies. This project is highly innovative – no other group in Australia has access to so many tissue sites. This project supports many early career researchers. Access to human tissue will put Doherty researchers at the forefront of their research fields nationally and internationally.

Allergy is the most common chronic disease, especially among children, and to date there are no curative treatments available. We have identified a corticosteroid-sparing agent derived from hookworm, that is orally bioavailable and that restores natural tolerance. We have found that this molecule specifically targets mesenteric lymph nodes and re-educate certain immune cells to allow them to “ignore” or “tolerate” allergens. This molecule suppresses allergic responses that take place in the airways and in the gastrointestinal tract. In order to further develop this groundbreaking finding to the clinic, we need to demonstrate that our initial findings also take place in humans.

T cells are important in controlling and clearing pathogens from our body. We have learnt a lot about T cells from the blood including which parts of the pathogen they target, how long they last, and which correlate with protection from disease. However, we know that not all T cells stay in the blood, and by looking at T cells in a range of tissues we can determine which immune cells are present, in what quantities, and what they are doing, to help us understand how they might be contributing to host protection or pathology. Together, this knowledge will help inform future therapeutic and vaccine design.

Our immune system helps to protect us safe from the many potentially dangerous pathogens in the environment. One important type of immune cells are B cells, the source of protective antibodies that fight infectious diseases as well as being key players in providing immunity against re-infection with the same pathogen. In this project we will use sophisticated molecular techniques to better understand how B cells are “programmed” to adapt to their local tissue environment to provide an immune response that is appropriate for the infectious challenge they are confronted with.

This research aims to create a model that allows the human spleen to be studied outside the body using organs donated for research. The spleen plays a key role in fighting infection and removing damaged blood cells, but is difficult to study in living people. By connecting donated spleens to a perfusion machine, researchers can explore how the spleen works in real time under normal physiological conditions. This will improve our understanding of immune diseases and infections, and support the development of new treatments to benefit future generations.

Sometimes a person can develop a severe reaction to a prescribed medication. These immunologically-mediated adverse drug reactions (IM-ADRs) can result in long-term side effects, morbidity and mortality. A subset of IM-ADRs are life-threatening and cause severe skin diseases such as Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN), and organ failure. While these severe T-cell mediated syndromes are often associated with specific HLA alleles, hypersensitivity generally occurs in only a small proportion of those carrying the risk allele. We aim to further understand the immunopathogenesis of disease and determine organ specificity in order to develop screening / prediction and prevention models for severe T-cell mediated drug hypersensitivity.