School of Medicine

•  Antenatal lung growth Impaired antenatal lung growth is a common outcome, pulmonary hypoplasia being found in 15-20% of early neonatal deaths. Reference ranges of normal lung growth have been established, mechanisms have been elucidated and interventions evaluated in various conditions associated with abnormal growth. We have investigated the role of diaphragmatic function in abnormal lung growth, particularly in infants with surgically correctable lung anomalies and developed novel tests of diaphragmatic function in neonates. We are currently evaluating the predictive value of new antenatal assessments with regard to chronic respiratory morbidity.
• Prevention of chronic respiratory morbidity following premature birth Chronic oxygen dependency and associated respiratory morbidity is unfortunately common following very premature birth. Factors important in the development of chronic oxygen dependency have been identified and prophylactic and treatment therapies examined, this has involved the development and evaluation of new techniques of respiratory support. Predictors of chronic lung disease have been assessed in order that prophylactic treatments can be most effectively targeted. Respiratory syncytial virus infection is associated with an increased risk of asthma in childhood in previously healthy infants and prematurely born infants suffer more severe acute RSV infection. Currently, the importance of initial airway size and genetic predisposition in determining the long term respiratory outcome in prematurely born infants who develop RSV infection is being assessed. Prematurely born infants are at increased risk of sudden infant death syndrome. As a consequence, the effect of posture and antenatal smoking exposure on respiratory control and function is being examined.
• Effect of chronic disorders on respiratory function in children Vital to diagnosis and appropriate treatment of respiratory morbidity is quantification of any abnormality, hence an important area of research has been the development of appropriate lung function tests for all ages, even those receiving intensive care. These tests have been used to facilitate management of young children with asthma and determine the impact of liver disease on pulmonary function. Two cohorts of children with sickle cell disease in South London and Jamaica are being followed. The prevalence of lung function abnormalities in these populations has been determined and ethnically appropriate reference ranges have been established. The role of asthma/reactive airway disease in the development of the acute and chronic respiratory complications in SCD have been determined and the efficacy of prophylactic anti-asthma agents is currently being explored.

Dr Hart's research is focused on (1) muscle wasting and rehabilitation (2) advanced physiological monitoring and (3) ventilation strategies in patients with chronic respiratory failure secondary to obesity, neuromuscular disease and COPD.

My professional background is in clinical psychology and neuropsychology. Since 2002 I have primarily worked in interdisciplinary academic rehabilitation with a focus on research and teaching. I am interested in cognition and rehabilitation in neurological disorders and the use of psychometrics to develop sound assessment and outcome measures for these conditions. I enjoy using both classical psychometrics and modern item response theory methods (Rasch aanalysis and Mokken scaling) in this work. I also have an interest in the development of a sound theoretical basis for interdisciplinary clinical and community rehabilitation. To date I have published 62 peer-reviewed journal articles, two invited journal articles and six book chapters.

Andrew Tutt is a Consultant Clinical Oncologist and Director of the Breakthrough Breast Cancer Research Unit and a Professor of Oncology at King's College London. After training at the Royal Marsden Hospital, he worked with Professor Alan Ashworth at the Institute of Cancer Research, where he described the DNA repair functions of the BRCA2 breast cancer predisposition gene. He practises clinical oncology at Guy's Hospital and has developed a translational clinical trial programme focusing on cancers associated with functional deficiencies in BRCA1 and BRCA2. His interests involve the discovery of novel therapies in BRCA1/BRCA2-associated cancers and ER/HER2-negative/basal-like breast cancers—including the identification of poly(ADP-ribose) polymerase (PARP) as an exciting new target for therapy in these areas. He is chief investigator for the international BRCA and Triple Negative Breast Cancer Trials (TNT) and the phase II ICEBERG proof of concept trials of PARP inhibition with Olaparib in BRCA1 and BRCA2 carriers. He leads a neo-adjuvant trial initiative for Triple Negative Breast Cancer in Breast International Group Neo-BIG program. Dr Tutt's laboratory research interests focus on the identification and validation of potential treatment targets and biomarkers for women with Triple Negative Breast Cancer.

The Mammary stem cell biology group focuses on characterization of normal and malignant mammary stem cells in order to elucidate their role in cancer initiation and progression.

Developing an experimental framework appropriate for the study of stem cells of human origin is one of the priorities of the group and an ongoing effort. Novel experimental systems are employed to understand the molecular mechanisms that govern cell fate decisions and to identify defects in these mechanisms that can lead to transformation. The ultimate goal of these studies is to develop clinical applications based on stem cell biology concepts and to explore their translational potential in cancer diagnosis, prognostication, therapy and
prevention.

The CAR mechanics lab is focussed upon development of novel genetic strategies to target T-cell specificity against diverse malignancies. The approach we use entails the construction of cDNAs that encode for fusions known as Chimeric Antigen Receptors (CARs). These molecules couple the ability to target native tumour antigens to delivery of a tailored T-cell activating signal. Delivery to polyclonal peripheral blood T-cells is achieved using retroviral or lentiviral vectors. In a parallel theme, we are developing systems to target other lymphoid cell populations against cancer, including natural killer and gamma delta T-cells. Our first clinical trial of CAR-based immunotherapy is scheduled for 2012 and will involve the treatment of patients with squamous cell carcinoma of head and neck.


Recent Publications:

1. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M (2002) Human T lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR/ CD28 receptor. Nature Biotechnology 20: 70-75. http://www.ncbi.nlm.nih.gov/pubmed/11753365

2. Maher J and Davies ET (2004). Targeting cytotoxic T-lymphocytes for cancer immunotherapy. British Journal of Cancer 91, 817-821. http://www.ncbi.nlm.nih.gov/pubmed/15266309

3. Lo AS, Gorak-Stolinska P, Bachy V, Ibrahim MA, Kemeny DM, Maher J (2007) Modulation of dendritic cell differentiation by colony-stimulating factor-1: role of phosphatidylinositol 3'-kinase and delayed caspase activation. Journal of Leukocyte Biology 82: 1446-54. http://www.ncbi.nlm.nih.gov/pubmed/17855501

4. Lo A, Taylor J, Farzaneh F, Kemeny DM, Dibb NJ, Maher J (2008) Harnessing the tumour-derived cytokine, colony-stimulating factor-1, to co-stimulate T-cell growth and activation. Molecular Immunology 45: 1276-87. http://www.ncbi.nlm.nih.gov/pubmed/17950877

5. Wilkie S, Picco G, Foster J, Davies DM, Julien S, Cooper L, Arif S, Mather SJ, Taylor-Papadimitriou J, Burchell JM, Maher J (2008) Re-targeting of human T-cells to tumour-associated MUC1 – the evolution of a chimeric antigen receptor. Journal of Immunology 180: 4901-9. http://www.ncbi.nlm.nih.gov/pubmed/18354214

6. Maher J, Wilkie S (2009) CAR mechanics: Driving T-cells into the MUC of Cancer. Cancer Research 69: 4559-62. http://www.ncbi.nlm.nih.gov/pubmed/19487277

7. Davies DM, Maher J (2010) Adoptive T-cell immunotherapy of cancer using chimeric antigen receptor-grafted T-cells. Arch Immunol Ther Exp. 58: 165-178. http://www.ncbi.nlm.nih.gov/pubmed/20373147

8. Wilkie S, Burbridge S, Chiapero-Stanke L, Parente-Pereira AC, Cleary S, van der Stegen JC, Spicer J, Davies DM, Maher J (2010) Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. Journal of Biological Chemistry. 285: 25538-44. http://www.ncbi.nlm.nih.gov/pubmed/20562098

9. Parente-Pereira AC, Burnet J, Ellison D, Foster J, Davies DM, van der Stegen C, Burbridge S, Chiapero-Stanke L, Wilkie S, Mather S, Maher J. (2011) Trafficking of CAR-engineered human T-cells following regional or systemic adoptive transfer in SCID Beige mice. Journal of Clinical Immunology. In press. http://www.ncbi.nlm.nih.gov/pubmed/21505816

Mr Michael Douek's translational research program evaluates novel devices and imaging modalities to improve breast surgery for cancer. This includes the clinical applications of nanotechnology for sentinel node biopsy, intraoperative radiotherapy and novel devises for breast reconstruction.

Mr Douek is the Chief Investigator of the SentiMAG trial of sentinel node biopsy and of the POBRAD trial (prospective trial of acellular dermal matrix for implant breast reconstruction). He is also Principal Investigator for the international randomised controlled trial of intra-operative radiotherapy (TARGIT trial), at Guys Hospital.

Another problems with islet transplantation is that the side effects of the anti-rejection drugs (immunosuppression) outweigh the benefits of improved glucose control in most patients. Therefore, most patients are not suitable for islet transplantation therapy and therefore must rely on insulin injections to control their diabetes. Microencapsulation of islets may allow transplantation of islets in the absence of immunosuppression. The islets are encapsulated in alginate, a polysaccharide derived from seaweed. The alginate forms a network around the islets, which is tight enough to prevent immune cells from making contact with the islets and killing them. The alginate network is, however, open enough to allow the diffusion of nutrients into the capsule and insulin out from the capsule. Therefore this can allow transplantation in the absence of immunosuppression therapy.

The aim of the research is to understand the molecular basis and anatomical pathways involved in leptin and insulin action and the role of the immune system and inflammation in obesity and the metabolic syndrome using both in vitro and in vivo models.

Autoimmunity in Type 1 diabetes: Type 1 diabetes is the result of the destruction of insulin-secreting pancreatic beta cells by a process in which autoimmune recognition of beta cell proteins is implicated. My research group has long-standing interests in the identification and characterisation of beta cell targets of the autoimmune response in Type 1 diabetes, with the view of developing strategies to identify individuals at risk for disease, and to apply antigen specific immune intervention to prevent disease progression in high-risk subjects. My group was the first to detect circulating autoantibodies to a tyrosine phosphatase-like protein, IA-2, in diabetic patients, and this antibody marker is now widely used for the prediction and diagnosis of disease. We have subsequently identified a region of the IA-2 molecule that is very commonly recognised by both ciirculating autoantibodies and T-cells in Type 1 diabetes. We are currently investigating the relationships between T- and B-cell responses to this and other regions of the IA-2 molecule, and the potential for this region to form the basis of antigen-specific vaccination protocols to prevent disease.

Development and function of pancreatic beta cells: IA-2 is a tyrosine phosphatase-like protein localised to secretory granules of pancreatic beta cells, as well as to secretory vesicles of a number of other neuroendocrine organs, including the pituitary. Our recent studies have shown that IA-2 is an important regulator of beta cell secretory granule content and insulin secretion. IA-2 is poorly expressed in fetal life, but is up-regulated after birth, in parallel with increases in islet insulin secretion in response to glucose. We are currently interested in understanding the changes in beta cell gene expression that occur during the functional maturation of pancreatic beta cells during their development, and the influences of hormones and environmental factors, particularly diet, on the development and function of the endocrine pancreas. These studies will aid our understanding of how early exposure to environmental factors can influence susceptibility to Type 1 and Type 2 diabetes later in life.

In vivo function of zinc-alpha2 glycoprotein (ZAG)
ZAG is believed to participate in the chronic weight loss and muscle wasting exhibited by certain cancer patients. ZAG's true in vivo function is as yet undetermined although given that the protein binds long chain fatty acids, it is likely that ZAG participates in lipid homeostasis. Using a series of biochemical and molecular biology based techniques attempts are being made to identify and characterize ZAG's cell surface receptor. Possible clinical applications of this research would be the development of drugs that inhibit or modulate ZAG:receptor binding, thus reducing or eliminating the drastic weight loss exhibited by some cancer patients during physiologically demanding therapies.

Recently my main focus has been the peroxisome proliferator-activated receptor genes, PPARα and PPARγ and the PPARγ target gene adiponectin. We have explored the effect of dietary fatty acid interaction with PPARG and PPARA variants on plasma lipids in the RISCK study, a randomised control trial in which a high SFA diet was replaced by MUFA or carbohydrate. We found significant diet x ADIPOQ gene x age interaction in determination of serum adiponectin. Habitual dietary P:S ratio x PPARG gene interaction and dietary fat x PPARA and PPARG gene interaction in determination of plasma lipids has also been shown. Ongoing investigations are centred on gene x diet interactions on lipid profiles and vascular properties related to n3-PUFA intake in the MARINA study.

2. PPARγ function in mitigation of lipodystrophic effects of anti-retroviral therapy (in collaboration with Dr Anne Mullen).

The use of anti-retroviral therapy can lead to HIV-associated lipodystrophy syndrome (HALS). There is some evidence that the activity of PPARγ is down-regulated by anti-retroviral drugs. Pharmacological PPARγ ligands such as rosiglitazone, have shown positive effects on HALS in some RCTs. We aim to investigate whether pre-treatment of cultured adipocytes with PUFAs alters the level of activated PPARγ extracted from cells exposed to anti-retrovirals. Promising results in vitro are expected to lead to human trials.

3. Functional and genomic changes following activation of TRPA1 receptors in the normal and hypertensive peripheral vasculature (in collaboration with Prof Sue Brain, Cardiovascular Sciences).

Research in mouse transcriptomics was initiated in an attempt to identify new players in energy regulation and obesity susceptibility. We originally investigated differential expression of hypothalamic genes in the dietary-induced obesity model C57BL6 mouse on high-fat and standard diets, using microarrays. The aim of our current collaboration is to determine how activation of peripheral vascular responses by transient receptor potential (TRP) ankyrin 1 (TRPA1) influences blood flow in the normal and angiotensin-II mouse model of hypertension to investigate the molecular and genetic changes that occur before and after activation of TRPA1 in the ear vasculature. We aim to identify genes and pathways that are affected by hypertension and/or exhibit selective altered expression following stimulation and are linked to the TRPA1 neurogenic peripheral responses in hypertension. Possible functional analysis in vivo will involve WT and TRPA1KO mice.

Recent publications

AlSaleh A, O'Dell SD, Frost GS, Griffin BA, Lovegrove JA, Jebb SA, Sanders TA (2011) Single nucleotide polymorphisms at the ADIPOQ gene locus interact with age and dietary intake of fat to determine serum adiponectin in subjects at risk of the metabolic syndrome. Am J Clin Nutr 94:1-8.

Lee AK, Kyriakou T, Weston AJ, O'Dell SD (2010) Functional single nucleotide polymorphism in acetyl-CoA carboxylase ACACB gene promoter. DNA Cell Biol 29:703-12.

Lee AK, Mojtahed-Jaberi M, Kyriakou T, Aldecoa-Otalora Astarloa E, Arno M, Marshall NJ, Brain SD, O'Dell SD (2010) Effect of high-fat feeding on expression of genes controlling availability of dopamine in mouse hypothalamus. Nutrition 26: 411-422.

Liu G, Riese H, Spector TD, O'Dell SD, Stolk R, Snieder H (2009). Bivariate genetic modeling of the response to an oral glucose tolerance challenge: A gene-environment interaction approach. Diabetologia 52:1048-1055.

Goyenechea E, Collins LJ , Parra D, Abete I, Crujeiras AB, O'Dell SD, Alfredo Martínez J. (2009) The -11391 G/A polymorphism of the adiponectin gene promoter is associated with metabolic syndrome traits and the outcome of an energy-restricted diet in obese subjects. Horm Metab Res 41:55-61.

Goyenechea E, Collins LJ , Parra D, Liu G, Snieder H, Swaminathan R, Spector TD, Alfredo Martínez J, O'Dell SD (2008) CD36 gene promoter polymorphisms are associated with low density lipoprotein-cholesterol in normal twins and after a low-calorie diet in obese subjects. Twin Res Hum Genet 11:621-628.

Kyriakou T, Collins LJ, Spencer-Jones NJ, Malcolm C, Wang X, Snieder H, Swaminathan R, Hart DJ, Spector TD, O'Dell SD (2008) Adiponectin gene ADIPOQ SNP associations with serum adiponectin in two female populations and effects of SNPs on promoter activity. J Hum Genet 53:718-727.

Ge D, Gooljar SB, Kyriakou T, Collins LJ, Swaminathan R, Snieder H, Spector TD, O'Dell SD (2008) Association of common JAK2 variants with body fat, insulin sensitivity and lipid profile. Obesity (Silver Spring)16:492-449.

Snieder S, Wang X, Shiri-Sverdlov R, van Vliet- Ostaptchouk JV, Hofker MH, Spector TD, O'Dell SD (2008) Associations with general and central obesity in post-menopausal women confirm TUB as a candidate gene for late-onset obesity in humans. Diabetologia 51:54-61.

My research focus is the development and application of statistical methods in human genetics, to identify and characterise genes contributing to common, complex disorders. Current research includes genome-wide association studies and disease risk prediction using genetic and environmental factors.

• Investigation of the genetic basis of susceptibility to common, complex disorders, including the inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and cancer.
• The role of genetic instability in susceptibility to acute myeloid leukaemia.

Much of my work centres on the genetics of breast cancer (especially where this is of an early onset, familial nature), and adopts several approaches:

A molecular analysis of the BRCA1 gene, which confers susceptibility to breast cancer in a proportion of women. This involves the investigation of the structure and expression of the gene product (including its role in sporadic breast and ovarian cancer), its regulation, and its behaviour as a tumour suppressor, and studies of transgenic mice with altered BRCA1 genes. Collaborative investigations of the structure of the RING finger domain of BRCA1 are also under way. 

The analysis of further genes implicated in the genesis of breast cancer, which exist in close proximity to BRCA1. Molecular analysis of the function, expression and regulation of these genes is gradually disentangling their complex relationship with BRCA1.

A sib-pair genome search, which aims to identify regions of the genome containing further genes predisposing to breast cancer, is being undertaken with Professor Cathryn Lewis.

I also have an interest in the PML/RARA translocation underlying Acute Promyelocytic Leukaemia, and with Professor David Grimwade am investigating the regulation of PML, and the structure of its RING finger domain.

My research is undertaken as part of the clinical arm of the Academic Rheumatology Research Group led by Professor David Scott at Denmark Hill though there is close collaboration with other Academic Rheumatology Group members, with other local Trusts and with the Rheumatology Specialty Group of the local Comprehensive Local Research Network.

The research is funded by a variety of agencies including Arthritis Research UK and the NIHR and involves both primary (trials and observational studies) and secondary (systematic reviews) studies.

Clinical research in inflammatory arthritis
1) Clinical trials examining the role and relative effectiveness of disease modifying drugs and biologic in rheumatoid arthritis and spondyloarthropathies
2) Observational research on patient-derived, clinical and other outcome measures and prognostic markers in inflammatory arthritis

Health services research in inflammatory arthritis
1) Patient's perspective of primary and secondary care rheumatology and musculoskeletal services
2) Evaluation of service improvements and innovation in inflammatory arthritis and other rheumatology services

Other musculoskeletal diseases
Similar projects in soft tissue rheumatic diseases

Main focus of research is that of immune regulation by heat shock proteins (stress proteins) in inflammatory disorders (mainly rheumatoid arthritis, inflammatory bowel disease and cardiovascular disease).

Modulation of inflammatory arthritis with the stress proteins HSP60 and BiP.

Antigen-specific CD4+ T cells appear to be a central component in the pathogenesis of a variety of human autoimmune diseases and animal models of autoimmunity. Such T cells can home to the target tissue where autoantigen is present and, after local activation, produce pro-inflammatory cytokines. These events lead to the recruitment and activation of both lymphocytes and monocytes that ultimately destroy the target tissue. Consequently, a search for antigens which could initiate and/or perpetuate T cell responses in arthritic joints is continuing. The characterisation of target antigens in autoimmune diseases is an important step towards understanding the aetiology of this group of conditions, and in designing specific immunotherapeutic regimes. Two such antigens identified in separate studies are the 60kD heat shock protein (hsp60) and the 70kD stress protein BiP. Surprisingly, immune responses to both these proteins are not pro-inflammatory but are instead classified as anti-inflammatory or regulatory. Hence continuing studies aim to utilise their regulatory potential to develop novel immunotherapeutic interventions in inflammatory diseases such as rheumatoid arthritis.

Circulating cell stress proteins, leukocyte function and cardiovascular disease.

There is growing evidence for the hypothesis that plasma levels of extracellular molecular chaperones, such as Hsp60 or Hsp70 correlate (positively or negatively) with susceptibility to coronary heart disease and stroke. The biological consequences of having high blood levels of such proteins are unknown. Nor have associations with subclinical coronary artery disease and risk of clinical cardiac events been established. Recent evidence has revealed that human lymphocytes are exquisitely sensitive to certain molecular chaperones with both activation and inhibition of cell function being found in vitro. The hypothesis being tested is that individuals with high levels of molecular chaperones in their circulation will evoke changes in lymphocyte function that may predispose to organ, particularly cardiovascular, pathology. This is being tested in studies combining molecular biological, immunological and epidemiological methods with cardiac imaging in a subset of the Whitehall II epidemiological cohort (a large group of civil servants who have had the development of any heart disease monitored over the past 15-20 years).

Our present laboratory projects focussed on BiP include the following:

Search for the cell surface expressed receptor(s) for BiPInvestigation of the mechanism by which BiP directly affects T cells and DC inducing regulatory T cells and tolerogenic DC respectively.Future work will incorporate projects looking at the efficacy of BiP in osteoporosis and transplantation where preliminary in vitro data shows that BiP has therapeutic potential

As a translational project BiP has preliminary approval by the MHRA for a PhaseI/IIa clinical trial.

• 'beta-selection', a point in development where gamma delta T cell differentiation diverges from the development of most alpha beta T cells.
• the demonstration that, by contrast to the systemic distribution of diverse alpha beta T cells, gamma delta T cells are disproportionately associated with epithelial tissues, wherein they reside as oligoclonal repertoires of limited diversity.
• the demonstration that gamma delta cells can promote immunoglobulin synthesis by B cells, but that this is primarily self-reactive. In 1998, I assumed the Professorship in Immunobiology at the King's College School of Medicine on the Guy's Hospital site. Our work has continued to provide insight, including:
• identification of the role played by the c-myc proto-oncogene in T cell development
• the demonstration that skin-associated gamma delta T cells protect the skin from potentially pathologic infiltrates of systemic lymphocytes
• the demonstration that gamma delta T cells are a component of the natural resistance to skin carcinogenesis.
• the demonstration that the gene expression pattern that best distinguishes gamma delta T cells from most alpha beta T cells is shared with an unusual set of tissue-associated alpha beta T cells that we collectively term unconventional T cells
• the identification of 'trans-conditioning', a mechanism by which unconventtional T cell differentiation is strongly influenced by alpha beta T cell progenitors.
• the demonstration that trans-conditioning may also affect the body's balance of effector and regulatory T cells Our current research interests focus on how repertoires of tissue-associated unconventional T cells develop and function, including the identification of novel host-encoded molecules expressed by epithelial cells with which gamma delta T cells interact. Research findings are being applied in the clinic, where we have just completed a proof-of-principle trial of gamma delta T cell therapy in hormone-refractory prostate cancer, in collaboration with F Dieli (Palermo).

Defining the molecular interactions and signalling events at the monocyte and endothelial cell interface in vivo

Clinical trials in HIV infection; especially immunopathogenesis, vaccine,metabolic and drug trials.

virus-host interactions during HIV-1 infections. Interests include host restriction factors, factors that support HIV-1 replication and the metabolic demand exerted by HIV infections.

The two main research projects focus on understanding mechanisms of staphylococcal (predominantly methicillin-resistant Staphylococcus aureus MRSA) disease pathogenesis and transmission in the hospital setting.
 

1. Identification of a highly bacteraemic strain of MRSA. During 2003/2004 the Trust had high rates of MRSA bacteremia. The result of a detailed epidemiological study identified that a significant reason for this was an extended outbreak on the ICU with a novel variant of MRSA, designated TW. This strain had an enhanced capacity to bind vascular access devices leading to bloodstream invasion. A targeted introduction of basic infection control and a novel decolonisation strategy led to termination of the outbreak. We have performed microarray-based analysis of this strain and are performing full genomic sequencing (collaborators Dr Jodi Lindsay, St George's University of London and Dr Julian Parkhill, Sanger Insititute, Cambridge). We are currently investigating the mechanism of adhesion and invasion in vitro which combined with the awaited genome sequence will potentially provide insight into the basic mechanism of MRSA bacteraemia and identify novel approaches to prevention. It may also identify genetic markers for hyperinvasive strains that can be used to assess the distribution of such strains across the UK for targeted enhanced infection control strategies.
2. MRSA transmission dynamics. Following the detailed ICU analysis it became apparent that our enhanced infection control efforts led to a sustained (more than 2 years) prevention of MRSA cluster outbreaks on the ICU and only a residuum of sporadic acquisitions. We are developing mathematical models of transmission dynamics through analysis of data from the ICU over the last 5 years to assess the reduction in risk of MRSA acquisition, assess the confidence with which the reduction can be ascribed to the enhanced interventions and to compare the transmissibility of different strains including TW in collaboration with Dr Ben Cooper, Health Protection Agency).

• Biomarkers of Tolerance in kidney transplantation: from 2003 till 2008 she coordinated a multicenter international endeavour to establish their existence. Now the focus is to translate into the clinic those biomarkers that are predictive of kidney transplant outcome. The aim is to enable biomarker-led individualisation of therapy using both genetic and immunologic monitoring techniques.
• Studying the role of B cells in transplantation tolerance.
• Long standing interest in characterising and quantifying alloimmune responses in humans.

• Natural Killer cells in transplantation
• T cell homeostatic proliferation
• Chronic allograft nephropathy
• Immunological memory in organ transplantation
• Interaction between complement and the adaptive immune response
• Regulatory T cells in transplantation
• Inter-cellular MHC transfer

Glomerulonephritis is a common cause of irreversible renal failure leading to the need for dialysis and transplantation. We aim to discover the fundamental causes of these diseases, in addition to the mechanisms that mediate renal inflammation. Our basic research program has used experimental models of glomerulonephritis to explore these mechanisms. In recent years we have dissected the role of the innate immune system and in particular how Toll-like receptors interact with the adaptive immune system and lead to tissue damage. We have also explored the role of specific IgG subclasses and Fc receptors in glomerular inflammation.

We are currently developing a specific interest in one form of glomerulonephritis, namely anti-neutrophil cytoplasmic antibody associated vasculitis (AAV). The figure below shows a glomerulus that has undergone fibrinoid necrosis and crescent formation, as would be seen in AAV. We are pursuing research based both on experimental models of AAV and on patient samples. Myeloperoxidase (MPO) is one of the major autoantigens in AAV and a model of AAV based on the knockout mouse has been published by others. We are using both this model and other novel systems to dissect both the mechanisms of capillary injury and the origin of autoimmunity in AAV. We are also collecting blood samples from newly presenting patients with AAV in order to examine how their white blood cells differ from controls, and to develop new markers of disease activity.

Current research includes: co-leading organisational case studies in Birthplace in England, a national study of birth outcomes in home, midwife led, and obstetric led units; investigating the relationship between measures of safety climate and health care quality in A and E and intrapartum care; and conducting nested process evaluations of two trials of obesity in pregnancy behavioural interventions.

I am programme director in the NIHR King's Patient Safety and Service Quality Research Centre leading a programme of work on innovations in service quality and health technologies. The programme of work on patient safety looks at both the translation of novel technologies into health care and innovative ways of organising services differently to bridge 'gaps' in care and improve quality and safety for patients. Current research includes: a) the exploration of the management of 'failure to rescue' in medical and maternity settings b) exploration of the development, diffusion, governance and patient experience of technique-centred and clinical innovation.