A fundamental discovery in immunology: Peter Gorer & murine H-2
Peter Gorer’s discovery of murine H-2 lies at the heart of cellular immunology, and provides a basis for understanding the immune response to infections, tumours, and transplanted organs, as well as autoimmune disease.
His legacy continues in the Division of Immunology, Infection and Inflammatory Disease, which conducts research over a wide range of interests. This research is being translated into understanding and treating many different conditions ranging from Type 1 diabetes, transplantation, rheumatoid arthritis and multiple sclerosis to HIV infection.
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A specific cellular response
With Pasteur’s rationalisation of Jenner’s pox prophylaxis (Pasteur termed it vaccination in honour of Jenner), it became clear that the body possessed protective mechanisms to fight the microbes that Koch and colleagues proved to be the causes of myriad diseases. The mechanism of protection was tackled by Kitasato and von Behring, who was awarded the Nobel Prize in 1901 for characterisation of antibodies in the humor; and by Metchnikoff, who, working with single-cell organisms and starfish larvae, demonstrated that cells that he termed macrophages could engulf and digest microbes.
Thus, there appeared to be not one but several distinct mechanisms of immunological protection. However, there was a critical distinction between the humoral and cellular responses as described by these great pioneers. Whereas Kitasato and von Behring showed that the antibodies were highly pathogen-specific, and varied among individuals according to prior infections, macrophages attack a broad range of microbes, and are broadly similar in all individuals from birth to death.
In short, they represent an innate response, whereas the antibodies reflect pathogen-specific adaptations to the burden of microbes that we confront in life. The question posed was whether there was a cellular component of the adaptive response, and if so, how it might work.
A critical step along the way to answering this question was provided in London in the 1930s by Dr Peter Gorer (1907-1961) whose work transformed immunology. Gorer identified several determinants of tumour cells to which the immune systems of inoculated mice would react. Because he had the rare foresight to realise the importance of raising and using genetically identical mice for his studies, he deduced that the second determinant, H-2, was not a tumour-specific response, but a response of one strain of mouse to the cells of another.
The relevant paper in 1937 is a tour-de-force of experimental reasoning, but itsfull significance was not recognised until well into the 1940s. Gorer had been appointed Reader in Experimental Pathology at Guy’s in 1947. Without teaching responsibility, and hence with almost total freedom to carry out research, Gorer sustained a powerful collaboration he had begun with George Snell at theJackson Laboratory in Bar Harbor, Maine. Snell had initiated his own studies of the genetics of histo-compatibility, which began to mesh extraordinarily with work on the blood-typing of mice with tumours resistant to the immune response that Gorer undertook during a year’s stay at Bar Harbor.
Together they demonstrated that the histo-compatibility locus responsible for Snell’s observations was one and the same as H-2 described by Gorer a decade earlier. A decade later, and the human equivalent of H-2, known as HLA, was characterised by Dausset, following which it was shown that the natural function of H-2/HLA is to bind to small fragments of microbes and present them for recognition to thymus-derived T-cells that compose the core of the cellular adaptive response.
Hence, H-2 lies at the heart of cellular immunology, regulating the body’s specific responses to infection, transplanted organs, and tumours, and, when awry, causing the body to attack its own tissues in autoimmune diseases such as Type 1 diabetes and multiple sclerosis, each of which is linked to genetic polymorphisms in H-2/HLA. Indeed, the whole science of tissue-typing that offers prognoses for transplant acceptance was born of Gorer’s work.
Snell, whose work on histocompatibility was awarded the Nobel Prize for Physiology or Medicine in 1980, described Gorer’s work in immunobiology as reinforcing his own discovery of H-2: ‘Dr Peter Gorer was the original discoverer of H-2,’ he said in his Nobel acceptance speech, ‘and although my own identificationof the complex was independent, our studies, once united, reinforced each other. Dr Gorer’s untimely death (in 1961) was a tragic loss to his many friends and to this field of science.’ Among them were several eminent researchers whom Gorer attracted to his research team at Guy’s, including Ed Boyse, Bernard Amos and Gustavo Hoecker.
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Promulgating the legacy
When a new research initiative in immunology was started at King’s in 1999, it seemed only appropriate to name it the Peter Gorer Department of Immuno- biology. Shortly afterwards, the Department was able to move into state-of-the-art laboratories, opened by Archbishop Desmond Tutu in February 2004. The new facilities are an active hub where almost 80 scientists research topics at the interface of infection and immunity. Building on the foundation of Gorer’s work, the Department is studying a second type of T-cell. Unlike conventional T-cells, these ‘gamma delta’ T-cells do not engage H-2/HLA.
This led to the hypothesis of the existence of a parallel system of recognition that may be particularly important in the response to certain infections, such as cytomegalovirus (which poses a major problem in the transplant clinic) and tumours. In collaboration with colleagues at Yale, gamma delta T-cells were unequivocally shown to be an essential component of the mouse immune response to chemically-induced cancer.
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Broadening the legacy
Together with five other departments, the Peter Gorer Department of Immunobiology forms the Division of Immunology, Infection and Inflammatory Disease (DIIID), whose goal is to understand the interplay between our immune systems and the infections, tumours, and autoimmune problems that afflict us. To this end, DIIID undertakes research across a broad spectrum of interests – from the adaptive response of B cells in the human gut, through characterising T-cell memory at the molecular level, to the description of the T-cells that promote Type 1 diabetes.
Research also spans the basic science laboratory, through the clinical laboratory and practice to the statistical assessment of clinical trial design in rheumatoid arthritis. The emphasis is on the translation of the discovery of important molecules and their roles into clinical applications. For example, a vaccine has been devised that may promote the transition of pathogenic T-cell specific for the pancreas in Type 1 diabetes, into protective cells that specifically suppress T-cells attacking the pancreas which has been identified in unafflicted siblings.
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Large scale immune problems
Research in the departments of DIIID in the fields of infection, renal medicine, and neuroimmunology are described in chapters 14, 19 and 6 respectively. The Department of Rheumatology is featured here as a further example of dissecting T-cell function in a human disease.
The Department’s main focus is rheumatoid arthritis (RA), among the most common of all autoimmune diseases, affecting more than 350,000 people in the UK alone, and several million worldwide. While the management of RA has recently been revolutionised by drugs such as infliximab that block the effects of the inflammatory agent, tumour necrosis factor-alpha, there is still scant understanding of its pathogenesis, essential to the development of disease-specific rather than generally immunosuppressive therapies.
Rheumatology research at King’s also has a great legacy. Alfred Baring Garrod (1819-1907), Professor of Materia Medica and Therapeutics at King’s in 1863, described the phenotypes of chronic arthritis and first coined the term ‘rheumatoid arthritis’. He also discovered the abnormal uric acid metabolismin gout. Within DIIID, the current Department of Rheumatology integrates basic and clinical research, focussing on how T-cells get into the joints, and determining ways in which these may also be converted into protective regulatory cells. In parallel, DIIID has sponsored a new strand of research investigating howmesenchymal stem cells may be provoked in situ to repair damaged joints. The intention is to couple such technology to highly specific anti-inflammatory regimens to effect complete rehabilitation of RA patients.
Drug and non-drug therapies are being evaluated using clinical trials and systematic reviews as well as correlating patient outcomes with novel genetic markers. The aim is to improve patient care by involving patients in their own treatment and introducing a ‘total quality care’ strategy. As such, the Clinical Trials Unit links basic research with outcomes research and currently acts as the coordinating centre for two international and three national trials, all aimed at improving treatment of inflammatory rheumatic diseases.
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Immunobiology not immunology
Assigning the name Immunobiology rather than Immunology to the new Peter Gorer Department, recognises the breadth of science that necessarily underpins contemporary progress in immunology. Researchers look not only at immune function but at the development of the immune system. One recent study unexpectedly showed that the cytokine, lymphotoxin, acts as a messenger co-ordinating the development of conventional T-cells with that of gamma delta T-cells.
Seemingly very basic research using cellular biochemistry and molecular biology to characterise ubiquitination, the process of tagging proteins for break-down, and proteolysis (the break-down process itself) may have an unexpectedly rapid pay-off in the finding that such processes appear to malfunction in Sezary syndrome, a variant of a cutaneous T-cell lymphoma. Such research highlights the cross-talk of DIIID with other units at King’s, such as the St John’s Institute of Dermatology, which likewise supports a key collaboration on the immunological underpinnings of psoriasis.
Recent genetic data from the Division of Genetics and Molecular Medicine points to a susceptibility to psoriasis on a region of the genome in and around HLA-C. Thus, less than 100 years after his birth, Peter Gorer’s extraordinary insights still illuminate the very modern facilities that support today’s research at King’s. The goal of that research is to scrutinise perceived wisdom in biomedicine; to develop and test novel hypotheses; and to advance our understanding of the basic causes of a wide range of diseases.
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Infection: fighting the age-old enemy
In the 1860s Louis Pasteur’s identification of the microscopic organisms that caused fermentation and putrefaction was a breakthrough in understanding infection. However, even before the mechanisms of transmission were properly understood, important advances were made in the control of infection in the operating theatre, the ward and the wider world.
Infectious disease remains a major cause of death in the developing world, and the area of South London served by Guy’s, King’s College and St Thomas’ Hospitals suffers from some of the highest rates of infectious disease in the country. Research at King’s today recognises two of the newest challenges posed by the ever-changing face of infectious disease – human immunodeficiency virus (HIV) and methicillin resistant staphylococci (MRSA). HIV is a devastating disease with 40 million globally affected. In 2005 alone there were five million new cases and three million deaths. Identifying the mechanisms of HIV infection, its treatment and prevention are the core of current infectious diseases research.
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Early work on infection
For centuries, diseases with a high mortality such as plague, smallpox, syphilis and tuberculosis were made more terrifying by the mystery of how they were transmitted. The scientific approach adopted by St Thomas’ physician Richard Mead (1673-1754) stands out from a history of quack remedies, astrological theories and charms against infection. His Short Discourse Concerning Pestilential Contagion and Methods to be Used to Prevent it was commissioned by the government in 1720 in response to a further threat of plague. At its peak, the plague in 1665 killed 6,000 people a week.
The statement helped toalleviate general panic and made a number of practical and theoretical innovations, such as the advice to separate the sick from the healthy (rather than quarantining a whole households) and the observation that fabrics could transmit plague (although the role of fleas was not yet known) leading to an early theoryof contagion.
Mead turned his attention to smallpox in the following year, when he conducted trials of smallpox inoculations among condemned prisoners at Newgate Prison. His report on these trials (1747) helped to establish the practice of inoculation in England.
In the following century, Samuel Wilks (1824-1911), a physician at Guy’s Hospital, was the first to observe that tertiary syphilis affected not only the internal organs such as liver, stomach and lungs, but also the skin.
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Lister and antiseptic surgery
Until the early twentieth century, all surgical procedures carried a high risk of death. Limbs injured by compound fracture were usually amputated due to fear of gangrene developing, yet half the cases still died. Abdominal surgery carried such a high risk of mortality that, apart from ovariotomy, it was banned at King’s College Hospital. It was thought that despite technical accomplishment, surgery on the chest, abdomen and brain would never be the domain of a surgeon’s knife. Joseph Lister (1827-1912) during his fifteen years at King’s, developed his practice of antiseptic surgery which changed the outlook for the future of surgery
In 1853, following medical training at University College London, Lister went to Edinburgh to take up a surgical post at the Royal Infirmary. In 1860 he was appointed Professor of Surgery at Glasgow Infirmary. It was during this time that Lister began to investigate the implications of Pasteur’s germ theory. Convinced that putrefaction was caused by airborne bacteria, he used carbolic acid-soaked bandages on wounds to create a barrier against infection. In 1867 he reported in The Lancet that of 11 cases of compound fracture so treated, nine had recovered – an excellent result for the time.
Lister was appointed Professor of Surgery at King’s College London in 1877 and continued to develop antisepsis at King’s College Hospital. On accepting the professorship he made it a condition that he should bring with him his house surgeon, William Watson Cheyne, a senior assistant, John Stewart, and two dressers, W M Dobie and James Altham, in order that his antiseptic methods could be carried out to his specification. He made surgeons wash their hands and instruments in carbolic acid before and after operations, wear clean gloves, swab incisions with carbolic and introduced carbolic sprays into the operating theatre. There was great resistance to these changes from a profession which had worn blood-soaked frock-coats as a mark of honour, as well as objections to the harsh effects of the carbolic acid which left surgeons with cracked skin.
Cheyne was an active supporter of Lister’s theories and contributed to them being recognised by the profession. In 1882 he wrote Antiseptic Surgery: its Principles, Practice, History and Results which was described by The Lancet as ‘a starting-point for the more general adoption of Mr Lister’s treatment’. Lister’s theory and practices gradually gained support from surgeons and by the mid 1880s there was a rapid increase in the use of his antiseptic techniques. This made possible more advanced lifesaving surgery, including brain and abdominal surgery (Lister was the second man in England to operate on a brain tumour). The technical knowledge already existed but practice had been defeated up to this point because of post-operative sepsis.
Lister finally abandoned the spray in 1887 but the influence of his theories was convincing. By 1910 postoperative mortality for major operations reduced from 40 per cent to less than three per cent and Lister’s principle – that bacteria must never gain entry to an operation wound – remains a basic principle of surgery to this day. Such was his contribution to the profession that surgery is often described as ‘before Lister and after Lister’.
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Florence Nightingale’s war on dirty hospitals
‘True nursing ignores infection, except to prevent it’ wrote Florence Nightingale (1820-1910) in Notes on Nursing.
Nightingale had been shocked by the filth, overcrowding and inadequate food provided in military hospitals during the Crimean War in 1854.
On her return, she found conditions little better in English hospitals. Nightingale confidently brought her experiences of the Crimea to the task of reforming hospitals.
Her Notes on Nursing (1859) redefined the job of nursing as a respectable profession, stressing discipline and cleanliness, and a year later she founded the world’s first professional nursing school at St Thomas’ Hospital. Nightingale also made recommendations for the design of hospitals and the layout of wards, and pioneered the use of record-keeping, statistics and epidemiological analysis to judge the success of her methods.
These improvements in hospital practice and conditions were paralleled by public health reforms such as the 1866 Sanitary Act which improved sanitary drainage (enforcing connection of all new houses to a sewer) and defined overcrowding as a nuisance, and the Public Health Act of 1875. Both acts were impelled by Sir John Simon (1816-1904), who trained at St Thomas’ Hospital and was Demonstrator of Anatomy at King’s College London, and surgeon at King’s College Hospital, before becoming the first Medical Officer of Health for London.
One of Simon’s great achievements was making smallpox vaccination compulsory for children in 1870.
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King’s continues its legacy of research into infectious diseases. The Department of Infectious Diseases is focusing its research on understanding and finding treatments for HIV, now one of the world’s most devastating infectious diseases. There is a particular opportunity, and responsibility, for King’s to investigate HIV. The College’s local area of South London has the highest rate of HIV incidence in the UK.
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Unlocking the body’s resistance to HIV
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As HIV-infected populations are monitored it has become clear that there are groups of patients who do not progress to AIDS. Detailed dissection of the immune response of these patients to the virus is another tool to understand the interaction between host and virus. A 12 year study of non-progressors by King’s researchers with collaborators in other centres has defined several novel immunological features in these individuals. Examples are an association between HLA alleles (DQ6) and the rate of decline of CD4 T-cells, and the selection of a unique T-cell receptor by HIV-specific T-cells.
The subtypes of HIV also influence the disease, and an epidemiological study of these and their effect on progression and response to treatment is ongoing in South London.
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Drug therapy for HIV
The outcome of drug therapy is variable, and King’s is collaborating in two large UK-based studies analysing factors affecting patients’ responses to treatment. Among those described are the rate of viral rebound after reduction in HIV load related to the antiviral drugs used, and the long-term probability of detecting HIV-1 resistance.
The clinical trials programme at King’s College and St Thomas’ Hospitals is evaluating novel antiviral agents such as the new fusion inhibitor, Fuezon, which prevents fusion of the virus with the cell; an antagonist of the CCR5 chemokine receptor; and new protease inhibitors effective against drug resistant isolates.
Black Africans and Caribbeans are diagnosed significantly later than the general population and an MRC-funded study at ten UK centres including King’s is examining the sociodemographic, behavioural and laboratory factors affecting the impact of HIV and its treatment on this section of the population.
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The ultimate aim to rid the world of HIV is the production of an effective vaccine.
Work to date has shown that DNA HIV vaccines are safe and well tolerated. An alloimmune HIV vaccine is undergoing evaluation. Vaccination by the mucosal route, mimicking the natural method of infection and involving the regional lymph nodes, is being evaluated.
King’s is a member of the Centre for HIV-AIDS Immunology at the USA National Institutes of Health, which was set up to examine the immunological barriers to vaccine development and to test new vaccines.
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MRSA – in the footsteps of Lister
MRSA (methicillin resistant staphylococci) has become a household name as a hospital acquired, sometimes fatal, infectious disease. In the UK in 2003, 953 patients died from this infection per annum, and the reported incidence of infection is 7,000 annually. Its descriptive name underlines its challenge as it is resistant to the range of antibiotics used to treat staphylococcal infections; this is a return therefore to the pre-antibiotic era for patients infected with MRSA.
Work at King’s is using molecular analysis of MRSA in a number of ways to reduce its impact. Rapid molecular typing methods have been developed to analyse and control outbreaks, to identify high level mupirocin resistance in MRSA strains and for rapid detection of MRSA in blood cultures. With colleagues at St George’s Hospital, the genetic basis of pathogenicity in different MRSA strains is being examined.
Researchers have shown that the contaminated hospital environment is a source of cross infection as MRSA can survive on dry surfaces for many weeks. Conventional cleaning fails to decontaminate these surfaces but gassing with H2O2 is effective.
From 2004, highly virulent community strains of MRSA with a predilection for children have developed and studies of the molecular epidemiology and control of these organisms have begun.
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