Do germs cause type 1 diabetes?

Germs could play a role in the development of type 1 diabetes by triggering the body’s immune system to destroy the cells that produce insulin. Scientists have previously shown that killer T-cells, a type of white blood cell that normally protects us from germs, play a major part in type 1 diabetes by destroying insulin producing cells, known as beta cells. Now, using Diamond Light Source, the UK’s synchrotron science facility to shine intense super powerful X-rays into samples, we found the same killer T-cells that cause type 1 diabetes are strongly activated by some bacteria. We hope this research will lead to new ways to diagnose, prevent or even halt the type 1 diabetes. Unlike type 2 diabetes, type 1 diabetes is prevalent in children and young adults, and is not connected with diet. There is little understanding of what triggers type 1 diabetes and currently no cure with patients requiring life-long treatment. In previous studies we isolated a killer T-cell from a patient with type 1 diabetes to view the unique interaction which kills the insulin-producing beta cells in the pancreas. We found these killer T-cells were highly ‘cross-reactive’, meaning that they can react to lots of different triggers raising the possibility that a pathogen might stimulate the T-cells that initiate type 1 diabetes. The research, published in The Journal of Clinical Investigation, provides a first ever glimpse of how germs might trigger killer T-cells to cause type 1 diabetes, but also points towards a more general mechanism for the cause of other autoimmune diseases.

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Scientists re-engineer body’s immune system for safer and more effective cancer treatment

We have used powerful X-ray technology to engineer an enhanced kind of white blood cell – known as a T-Cell– capable of targeting cancerous tissue while minimising contact with healthy tissue, which can be fatal to patients receiving this kind of experimental therapy. Targeting cancer using T-cells is a growing therapeutic area. They are however limited in their cancer-fighting potential, owing to their inability to attack the body’s own tissue. This is a major obstacle for researchers trying to target cancer cells which often derive from healthy cells. To overcome this, we used an enhanced, modified T-cell receptor (TCR), a molecule on the surface of T-cells that acts like highly-sensitive fingertips that probe the body for signs of disease. This approach is currently being trailed for a wide range of cancer targets, but remains potentially dangerous to trial participants. Exploiting a technique known as X-ray crystallography – the same technique used to solve the structure of DNA – we demonstrated how a modified TCR, which was intended to target a cancerous antigen, mistakenly began attacking healthy heart tissue. The synchrotron enabled us to visualize this interaction between the engineered TCR and the cancer and heart tissue markers, to reveal that at an atomic level they were both similar in shape, making it extremely difficult for the T-cells to differentiate between the two.

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T-cells 'uproot' a cancer peptide to target melanoma

A team from Cardiff University, led by Dr David Cole and Professor Andrew Sewell, have previously shown that T-cells are so sensitive, they can ‘spot the difference’ between cancer cells and these modified peptides. As a result, T-cells selected with the modified peptide do not always have the ability to ‘see’ the original cancer cell. To shed more light on the molecular basis for this T-cell sensitivity, the team recently visited Diamond Light Source – our national UK synchrotron facility, and used X-ray crystallography to visualise the interaction between a T-cell and a natural and modified skin cancer derived pMHC at atomic resolution. Their results, published in the European Journal of Immunology (link to:), demonstrate that the T-cell antigen receptor can ‘tug’ on the natural skin cancer marker, subtly changing its shape. This molecular change did not occur with the modified skin cancer peptide, explaining how T-cells might differentiate between the two. This new mechanism of T-cell discrimination helps to explain why T-cells selected by the modified cancer vaccine might not recognise the natural epitope on skin cancer cells.

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How X-ray crystallography saved your life and sent you to the moon

Dr David Cole has been awarded £56K by the Wellcome Trust to develop a public engagement programme with Techniquest science museum in Cardiff Bay. This public engagement activity will comprise of a mobile planetarium show (how small is small and how do T-cells work), workshops (solving a crystal structure and helping T-cells to fight cancer), two standalone table-top exhibits and a series of public lectures aimed at a more adult audience. These activities will demonstrate why X-ray crystallography is such a powerful technique, and how it can be used to learn how our immune system functions (leading to new medicines). The main aims are to provide young researchers with experience and training of public engagement, and inspire the next generation of UK scientists.

Counting the seconds for immunological tolerance

An article appearing in the latest edition of the journal Cell discusses how immunological self-tolerance develops. The article was published by the research group led by Professor Ed Palmer and first author Ondrej Stepanek from the Department of Biomedicine at the University Hospital and the University of Basel along with Prof Andrew Sewell and Dr David Cole from Cardiff (UK) and colleagues from Cambridge (USA). During their maturation process, T cells in the thymus undergo various tests requiring T cell's antigen receptor to bind the body's own molecules. If the antigen receptor binds a body molecule too tightly, the developing T cell might eventually cause an autoimmune disease; in this case negative selection is triggered, and the cell dies. Only those T cells that exhibit "loyal" behavior towards a person's own body continue the maturation process, to become pathogen-fighting T cells.

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Seeing is Believing: What Molecular Immunology still has to show us

How do we know that major histocompatibility complex (MHC) molecules can bind to peptides, or which bit of the T-cell antigen receptor (TCR) enables T-cells to stick to aberrant cells? How have researchers been able to make enhanced peptides vaccines, or enhanced affinity TCRs for targeting HIV and cancer? These advances, and many others, have only been possible because of a few molecular immunology techniques that some may find a little inaccessible – namely: X-ray crystallography and molecular biophysics.

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X- Ray Crystallography

It's been described as 'the breakthrough science': the study of crystals and their structure. And it's led to some of the most significant scientific findings of the last century such as revealing the structure of penicillin and DNA. This year is the International Year of Crystallography and the centenary of the discovery of X-ray diffraction. So Science Cafe decided to take a closer look at its history and achievements.

Adam Walton is joined by leading Welsh Chemist Sir John Meurig Thomas and science writer and broadcaster Georgina Ferry, who talk him through the personalitlies and breakthroughs in crystallography. Sir John has written widely about the remarkable Bragg father-and-son team whose pioneering work revolutionised our understanding of solids. Georgina Ferry has written the biographies of two important crystallographers; Max Perutz and Dorothy Hodgkin.We also take a trip to the Cardiff laboratory of Dr Pierre Rizkallah, where the technique is being used today to find new drugs to treat cancer.

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Diamond: Britain's answer to the Large Hadron Collider

At the Diamond particle accelerator in Oxfordshire, experiments using beams of light 10,000 times brighter than the sun have implications for the fight against cancer, improved air safety and energy efficiency.

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Engineering TCRs to target to cancerous cells

Using technology developed by partners, Immunocore. Molecular visualisation using X-rays (the technique used to solve the structure of DNA) enabled them to understand how this molecule targets melanoma cells with high specificity and affinity.

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Hi-jacking’ the body’s killer cells could help fight cancer

Hijacking’ cells in the body that normally attack common infections to target cancer instead could offer the body a ready-made army against the killer disease, a team led by Oxford-based biotech company Immunocore Limited and Cardiff University researchers have uncovered.

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Scientists shed new light on link between ‘killer cells’ and diabetes

Killer T-cells in the human body which help protect us from disease can inadvertently destroy cells that produce insulin, new research has uncovered.

The study provides the first evidence of this mechanism in action and could offer new understanding of the cause of Type 1 diabetes.

Professor Andy Sewell, an expert in human T-cells from Cardiff University’s School of Medicine worked alongside diabetes experts from King’s College London to better understand the role of T-cells in the development of Type 1 diabetes.

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Interview with Discovery Magazine

Florian talks about his Tenovus funded research

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Wellcome Trust Research Career Development Award for Dr David Cole

Dave Cole has been awarded 5 years worth of funding (£771,080) to study the structural and biophysical parameters that govern T-cell receptor binding to peptide-major histocompatibility complex class II, and how this interaction can be modified in order to develop therapies and enhanced diagnostic tools directed at CD4+ T helper cell mediated immunity.

Could T-cells hold the key to curing cancer? (Wales Online)

Health Wales is highlighting the work of Welsh Crucible researchers – the cream of Welsh research talent. Dr David Cole explains his research and why T-cells could hold the key to curing cancer.

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Professor Sewell speaks at Juvenile Diabetes Research Foundation meeting

The University’s latest research into Type 1 diabetes will be outlined by a Cardiff scientist as part of a local conference.

Professor Andy Sewell of the School of Medicine will speak at the Juvenile Diabetes Research Foundation and Diabetes UK Cymru Open Meeting on 21 November 2009.

Science in Health Day

We run sessions as part of the annual ‘Science in Health Day’ at Cardiff University.

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£3m BBSRC Award

Research into immunity and infection at Cardiff University has been given a multi-million pound boost with a major award from the Biotechnology and Biological Sciences Research Council (BBSRC).

Seeing how we see cancer

A molecular image revealing the interaction between skin cancer cells and T-cells – the cells which protect our body against disease - has been produced by the School of Medicine.

NEW - Molecular structure of the best-studied human cancer T cell antigen revealed

We have used X-ray crystallography to determine the structure of the best ever studied human cancer antigen in complex with a human T-cell receptor. This 'antigen' molecule is upregulated on the surface of human melanoma cells and enables killer T-cells to identify and eliminate these cancerous cells using their T-cell receptor. We anticipate wide interest in this structure as it is only the second human cancer/T-cell receptor complex ever solved. Our T-cells are really designed to eliminate 'foreign molecules' and they are crucial for the elimination of pathogens. T-cells perform less well at eliminating cancer as cancer cells are derived from our own tissue and pose the immune system a greater challenge. A link to the paper, published online at The Journal of Biological Chemistry can be found below:

Cole DK, Yuan F, Rizkallah PJ, Miles JJ, Gostick E, Price DA, Gao GF, Jakobsen BK, Sewell AK.
Germline-governed recognition of a cancer epitope by an immunodominant human T-cell receptor.
Journal of Biological Chemistry. 2009 July. Ahead of Print.

Visualising cancer interactions

A molecular image revealing the interaction between skin cancer cells and T-cells – the cells which protect our body against disease - has been produced by the School of Medicine.


An Immunologists 10 commandments (Immunology News)

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Advances HIV

Download the Spring 2009 edition of Advances - The Journals for Science, Engineering and Technology in Wales

TOP STORY - Bionic T-cells kill HIV

We have recently published a groundbreaking study in Nature Medicine that utilises engineered T-cells which can target and kill all natural escape variants of HIV in vitro. This discovery has attracted worldwide interests and has been covered by a number of mainstream publications and news broadcasters!! Links can be found below:

A2 Mel