MRC Human Immunology Unit
Centre profile from the MRC Network publication issued Winter 2005.
The increasing globalisation of infectious disease is a major challenge to human health. The MRC Human Immunology Unit is a key player in international efforts to combat this threat, and in research into other diseases involving the immune system.
The Weatherall Institute of Molecular Medicine, where the HIU is based (right)
The immune system is crucial to human health. Our ability to identify and destroy invading pathogens involves complex networks of interacting cells and molecules. Understanding precisely how the system works at the cellular, genetic and molecular levels will help in the development of new therapies for diseases such as AIDS, avian flu, multiple sclerosis, arthritis and eczema. This is the business of the MRC Human Immunology Unit (HIU) based at the John Radcliffe Hospital in Oxford.
It is no coincidence that the unit sits only a few yards from the bustling entrance of one of the world’s most famous teaching hospitals: the work of the unit lies squarely at the intersection of fundamental molecular science and clinical research.
Creating the big picture
The HIU, located in the Weatherall Institute of Molecular Medicine, was founded in 1998 under the directorship of Professor Andrew McMichael as a merger of two MRC programme grants, involving three senior MRC clinical fellows, a Wellcome Trust senior fellow, and a scientist recruited from Denmark, Lars Fugger.
“The unit’s initial interest was on how the immune response deals with viruses, with a big but not exclusive focus on HIV,” says Professor McMichael. “We subsequently broadened it to cancer immunology and studies on autoimmunity, with a strong core of basic immunity work.”
The HIU now has eleven research groups and employs about 100 staff in total and has an annual budget of between £3.5m and £4m, which includes funding from both the MRC and external sources. While each of the groups carries out its own research, often into diverse aspects of the human immune system, all the research is contributing to a single ‘big picture’ of human immunology, and much of the work is complementary.
HIV, influenza and the immune response
Four HIU research groups – led by Professor McMichael,Tao Dong,Tomas Hanke and Xiao-Ning Xu – study the human immune response to HIV.
“A lot of the work is trying to understand why patients who are infected with HIV can progress to disease very differently,” says Professor McMichael. “In some people disease progresses very rapidly, while others can survive for 15 to 20 years.” One promising line of research has been into a protein produced by the virus called Nef, which subtly alters the surface of infected cells. This ‘camouflages’ the cells, so that the immune system does not recognise them as being infected and the virus survives and replicates.
The HIU has been involved in the development of a number of candidate vaccines for HIV that are currently in various stages of clinical trials. It is also part of a large international programme that was recently launched with funding from the USA National Institutes of Health to look at how the immune system responds during the very early stages of infection. In some people the virus gains a foothold early on and is present at relatively high levels, whereas in others the initial levels are much lower. “We think the immune response is playing an important role in setting these initial levels, which can have a significant influence on the subsequent progression of disease,” Professor McMichael says. “If we can identify the features of a good immune response as against a poor one, we can use this knowledge to help us design more effective vaccines.”
The extensive work on HIV has yielded important insights into viral infections generally, including avian flu and the virus that causes SARS (severe acute respiratory syndrome). One important question with these diseases is whether it is the virus itself that is causing people to die, or whether it is the immune response that is the problem. As Professor McMichael observes, “It could be that the virus is sitting harmlessly in the body’s cells, but that the immune system overreacts in some way.”
Researchers in the unit have recently started a collaboration with colleagues in Vietnam, where techniques developed in the HIV work will be applied to the avian flu virus.
Professor John Bell’s group, meanwhile, is making significant advances in understanding the immune response to the influenza virus. When a virus invades the body, fragments of its protein coat are presented as antigens to the immune system. In influenza there appears to be a common response by Tcells in most individuals, suggesting that certain antigens are crucial, or “immunodominant”. Antigens are the central component of vaccines, and the development of effective vaccines relies on the identification and isolation of key antigens.
Tcell biology group
The group led by Professor Simon Davis and Dr Ed Evans is investigating the mechanisms by which Tcells are initially activated – a central event in the immune response. When the antigen – a protein fragment from a virus, for example – is presented to a Tcell receptor, a biochemical trigger is pulled. Professor Davis and his colleagues believe that the status of the receptor is determined by a delicate balance between two antagonistic chemical processes occurring at the receptor protein called phosphorylation and dephosphorylation.These processes are carried out by enzymes called phosphatases and kinases, which normally have equal access to the receptor.When the antigen is presented, however, it effectively barges the phosphatase out of the way. “We believe that this exclusion of the phosphatase upsets the balance of phosphorylation and dephosphorylation, which acts as the trigger for the activation, kicking off the proliferation of Tcells,” Professor Davis says.“What this suggests is that we might be able to use other ways to cause the segregation of the phosphatase from the receptor – with antibodies, for example – and thereby manipulate the signalling process to either increase or decrease Tcell proliferation.”
Immunological origin of arthritis
Dr Paul Bowness’s team is studying the immunological origin of certain forms of arthritis, and in particular ankylosing spondylitis, which usually occurs in young men and results in swollen joints and a painful back. More than 95 per cent of sufferers have an unusual type of HLA molecule on the surface of their cells. HLA is a protein that occurs on cells in the body, enabling them to communicate with the immune system. The team is trying to understand why the presence of this particular variant of HLA, called HLA B27, hugely increases the chances of getting the disease. “These molecules are important in helping the body fight off viruses, and this particular one is especially good,” Dr Bowness says. “We think that the abnormal form of the molecule stimulates the immune system in an abnormal way, resulting in the production of molecules that cause damage and inflammation. If we can identify the form of the molecule that is causing the problem and then block it, we might be able to ‘switch off’ the arthritis.”
Cutaneous immunology
Dr Graham Ogg is interested in the immunology of the skin and his group has made a potentially significant breakthrough in the understanding of what causes eczema.“We believe that the root cause could be because some people have increased populations of a common bacterium, Staphylococcus aureus, on their skin,” Dr Ogg says. Most of us have this organism present on our skin, but people with eczema appear to be partially deficient in the natural antimicrobial defences, which allows the bacterium to proliferate. The presence of so many of these bacteria stimulates skin cells called keratinocytes to produce so-called HLA class II molecules on their surface, which are otherwise not present. The HLA molecules in turn grab on to fragments of proteins from house dust mites, dog and cat fur, and pollen, and present them to the immune system as harmful foreign invaders. “Tcells then release substances to react to what are apparently infected cells, causing inflammation,” says Dr Ogg. “If our ideas are correct, this has clear implications for the treatment of patients, by reducing the bacterium population on the skin and the amount of allergens such as dust mites.” The team hopes to begin a clinical trial shortly.
Immune-cell trafficking
A key aspect of the human immune system is the constant movement of immune cells between the blood and tissues, and between tissues and the lymphatic system, a network of vessels running throughout the body that carriesinfection-fighting cells.“These events are pivotal to the inflammatory process and are fundamental to generating an immune response,” says Professor David Jackson, who leads the group that studies this type of cellular trafficking. Understanding the processes involved at the molecular level could lead to new ways of controlling inflammation, for example, or help in the generation of vaccines.
Migration of immune cells across the lining of blood vessels and into tissue involves a protein receptor on the surface of the cells called CD44, which binds to a large carbohydrate molecule called hyaluronan, or HA. In pioneering work, Professor Jackson’s group, together with Professor Martin Noble at the Laboratory for Molecular Biophysics, University of Oxford, has crystallised CD44 and determined its three-dimensional structure. The group has also bound together CD44 and HA, crystallised the resulting structure and elucidated its 3-D characteristics. “In this way we have shown exactly where the interaction between the two molecules occurs and we understand what kind of interaction is involved,” Professor Jackson says. “This allows us to design small molecules that could interfere with the process.” The group has also made important discoveries that have allowed lymphatic vessels to be extracted from tissues and reconstituted in the laboratory.
Tumour immunology
Professor Enzo Cerundolo's laboratory studies how the immune system recognises cancer cells, with the ultimate aim of developing vaccines against cancer. The idea behind a cancer vaccine is to present the immune system with antigens specific to different types of tumour so that the body can arm itself in advance and recognise and destroy rogue cells before they become established.
“There are three main issues,” says Professor Cerundolo. “We need to learn how to immunise, we need to be able to monitor the immune response, and we need to identify the antigens.” The team has achieved the latter two, and the big challenge is to learn how to package the antigen in such a way that it can get into the body and stimulate the immune system correctly.
The team is adopting a ‘prime-boost’ approach, where synthetic antigen proteins are first presented to the body in a special mixture of chemicals to ensure a powerful initial response, followed by a ‘boost’ in which the antigen is wrapped within a harmless virus. The team has worked extensively on melanoma and is now looking at colon and prostate cancer.
Mechanisms of autoimmunity
Professor Lars Fugger’s team is trying to understand why the body’s immune system sometimes fails to differentiate between an invading pathogen and the body's own cells in autoimmune diseases such as multiple sclerosis (MS). By the very nature of their job,Tcells must be highly adaptable in order to recognize many different antigens, but this also makes the system inherently prone to mistakes. It appears that multiple sclerosis occurs when a variety of genetic and environmental factors combine in a particular way. “The only identified genetic risk factor associated with MS relates to certain HLA genes,” says Professor Fugger. “We are trying to identify the function of the individual genes. Overall there appears to be an interplay between a certain Tcell repertoire, environmental factors such as viruses, HLA genes and other, unidentified genes.”
The work of the HIU demonstrates just how complex the human immune system is, involving precise interactions between cells, molecules and genes. Slowly but surely its researchers are beginning to piece together this immensely detailed jigsaw, constantly improving our ability to treat debilitating diseases and combat life threatening infections.