The Centre was officially launched on 6 June 2104 by Olympic gold-winning rower Katherine Grainger in the stunning surroundings of Glasgow City Chambers. Watch the short film about Our launch here.
The project aims to identify
- Why Rheumatoid Arthritis begins
- Where it starts and why it attacks the joints
- Why it persists
- Whether we can develop new treatments
It will do this by
- Bringing together researchers from three leading universities
- Recruiting the best young scientific minds
- Engaging with patients to guide our research
Year 1 progress report
The core objectives of our Centre of Excellence are
- To establish the immunobiology of the earliest events that triggers rheumatoid arthritis disease (RA).
- To identify why this is not resolved allowing the disease to progress to a chronic state.
We have identified two key programmes which will help us to meet these objectives
1. The pathogenic, autoantigen-driven immune response in RA
Rheumatoid arthritis arises in part from the immune system reacting to, and causing damage in our own tissues, especially the joints – normally the immune system reacts only against foreign bodies like bacteria and viruses and accepts our own tissues as normal. We have been working to understand why the immune system becomes confused and appears to treat the normal structures of the joint as ‘foreign’.
One potential part of the body that could contribute is the thymus – in essence this is the part of the body that teaches immune cells to recognise our own tissues and not to react to them. We have now defined the cells in the thymus that participate in this teaching process – if we could now learn to control them then this would allow us to ‘re-educate’ the immune system using the thymus and potentially generate long lasting therapies.
In addition, in the joints themselves, the key cells that make these decisions are called dendritic cells. These are especially sophisticated and act as gatekeepers for the immune response - if they behave abnormally they could allow the start of damage. The studies we have undertaken demonstrate what these cells look like in RA and we have set up models that will allow us to try to manipulate these cells to restore the immune system to normal..
These studies are directly underpinning dendritic cell based therapies that are ongoing in Newcastle and so these may lead to new cellular or molecular therapies.
It is hoped that these studies could lead to the development of a new type of medicine that will re-educate the immune system to accept the damaged tissues of the joint in people with rheumatoid arthritis. These treatments could provide long lasting benefit or even the state of remission without the need for medicines in the long term. Over the next year we plan to expand these studies bringing together the full capacity of the three hub Universities in the Centre – we have invested in studentships and shared technologies to enhance this area of research.
Finally, biomarkers (molecules that we have found in models of arthritis but which might be useful as indicators of likely response to a particular treatment) have been identified from work that is ongoing in Glasgow. These will shortly be used in a clinical trial in which RA patients will be treated with abatacept (Orencia) to establish the way in which that medicine works in RA.
2. The molecular orchestration of synovial inflammation in RA
This programme seeks to understand what it is about the synovial (joint lining) cells in RA that make the joint a place in which white blood cells can survive, promote inflammation and cause damage. The studies performed in the last year identify why specific white blood cell types can be switched on, and are unlikely to switch off. A critical part of RA is the failure of the inflammation that starts in joints to properly switch off. Thus it appears that the joint linking layer cells have particular properties to promote inflammation. They could therefore become targets for new therapies – one possible approach will be tested shortly in a clinical trial in which a medicine that has been shown to block cancer cell growth will be given to people with RA to see if we can recapture the same benefit by blocking growth of joint linking cells.
In other studies, we have identified the pattern of genes that are switched on in other white blood cells. One type of cell, a macrophage, has attracted our attention– this is a cell type that has been targeted by current biologic treatments such as TNF and IL-6 inhibitors. In the last year we have found several new tiny molecules that appear to control the pathways inside macrophages that allow them to be switched on and again fail to switch off. These pathways are also now being explored in the dendritic cells described above which can act as the gatekeepers for the immune system. In this way we are linking our discoveries in Themes 1 and 2.
Although our studies are at an early stage we are planning a clinical trial that will attack the joint lining cells. In the longer term we hope that some of the pathways we have found that allow the joint lining layer cells to enhance the survival and inflammation caused by white blood cells may offer new treatment targets.
We have an ambitious plan that will explore the behaviour of subsets of the lining layer cells taken out of the joints of people with RA. These cells will be examined for their ability to support the survival and function of various types of white blood cell. We will especially look at macrophages and B cells since both of these types of cell have been related to the causes and perpetuation of RA In both cases a more detailed understanding of their activities could lead to new therapies – or at least signs that could guide treatment. Finally we will balance these studies with more detailed examination of macrophages taken directly out of the joint, and dendritic cells taken from the joint and the blood of patients. These final experiments will match those being performed in theme 1, optimising the programmes across the Centre.
Year 2 progress report
Our team has continued to research a number of different aspects of the disease in the search for a cure for rheumatoid arthritis. A summary of the key findings under each of our 3 programmes is given below.
The pathogenic, autoantigen-driven immune response in RA
- The thymus is an organ in the body which controls the generation of a group of white blood cells called T cells and whether T cells are able to recognise and potentially respond to our own tissues – the loss of control of T cells that can attack our own tissues are thought to be important as a possible cause of RA. The function of the thymus has not been very well explored in the context of inflammatory arthritis as yet. One group of researchers is currently developing models that will allow the role of the thymus to be explored in detail at different stages of the development of arthritis. These studies will act as forerunners to cellular analyses in patients with RA that may help determine the role of thymus in adult human disease. These experiments are at a pre-clinical stage and will not directly impact care at the moment. However, they are essential as we move towards the concept of tolerance-inducing therapies, re-educating the immune system not to attack our own tissues. If these approaches are successful, it would mean short-term treatments could help to achieve long term remission in people with RA.
- Several lines of investigation are also examining the biology of T cells themselves in the context of RA. Perhaps closest to the clinic at present is the work in which a molecular signature is emerging in the T cells of patients with early RA that points to a specific inflammatory pathway as critical in disease. This pathway mediated by an inflammatory protein called IL-6 appears to be a key ‘on switch’ for these T cells. This offers a new therapeutic rationale for IL-6 inhibition in very early RA, and a possible biomarker from a blood test that can identify patients more likely to respond to that kind of treatment. In parallel some early studies suggest that T cells from people with RA may be older than their years – ie they act more like cells from people very much older than the actual age of the patient. This may promote disease and is being actively investigated.
- The last strand of this programme seeks to understand the behaviour of a further white blood cell type – the dendritic cell that has a fundamental role in educating the immune system as to what should and should not be considered an infectious challenge. If confused, these cells may trigger immunity against our own self-proteins and therefore trigger autoimmunity, as we see in RA. The current studies are embarking on an analysis of the different types of dendritic cells (there are likely to be several types) that should shed new light on the very early decision the immune system makes in the development of RA.
These studies are at an early stage and the T cell signatures in early RA are the closest at present to clinical application. The remainder of these studies is setting the groundwork for tolerance-inducing and preventative studies which will be undertaken in the future. If successful, the T cell signature will select patients in early phases of RA that are more likely to respond to a given therapy, resulting in improved clinical responses. If we do establish the reasons for loss of immune tolerance (or recognition of our own joint tissues) then we can move to highly specific preventative therapies in due course.
The work programme will continue with our results being disseminated at scientific and public engagement meetings as we become confident in our findings. The ICoSRA study is a current clinical trial to examine some of these events using a drug called abatacept (orencia) in patients. This will report in 2017. The purpose of this study is to directly examine the effect of this medicine on the T cells in people with RA to shed new insight to their biology in disease. This will feed back to the discovery work described above.
The molecular orchestration of synovial inflammation in RA
This programme has made substantial progress in exploring events within the synovial membrane of people with RA. The work has several strands, each interwoven.
- B cells are a type of white blood cell that make antibodies, and also release inflammatory proteins called cytokines. The advances in knowledge about the B cell role in RA is significant. Work in the Centre has identified a new biomarker for B cells that seem to have a particular role in driving the inflammation associated with RA. This new biomarker provides a potential therapeutic target. In parallel, we have also discovered a small epigenetic regulator, or microRNA, that is important in allowing these cells to grow and mature and become potentially dangerous in the context of RA.
- Further studies continue to describe the resident cells that make up the lining of our joints – the fibroblast. We are taking several lines of investigation – some to look at the metabolism of these cells in RA, others to look at the physical and molecular appearances, others to examine how they ‘talk’ to invading white blood cells. Together we are building a picture of the way in which the cells that normally are building blocks of a healthy joint can become conspirators in the disease by contributing to the damage, by releasing enzymes or destructive proteins that attack cartilage and bone, and also by becoming perpetual and able to promote chronicity. It is likely that these cells are an important reason for RA not switching off, which in terms of established disease is a vital question.
If consolidated, we are hopeful that a new therapy will emerge based on the identification of a new type of B cell that is related to RA pathogenesis. We are also optimistic that by properly characterising the resident fibroblasts in the joint tissue we can develop completely new therapies aimed at normalising the joint environment and thus encouraging maintenance of remission once achieved.
We will continue to generate new data and to consolidate our findings into scientific publications that will also be communicated to the ARUK and relevant patient groups via our outreach programme. In due course we will seek opportunities to develop new medicines in close collaboration with the charity.
Arthritis Research UK
Arthritis Research UK is the biggest funder of world-class research into the cause, treatment and cure of all forms of arthritis in the UK and conducts scientific and medical research into all types of arthritis and musculoskeletal conditions. Its core remits is funding research and providing a comprehensive range of information for patients, the public and health professionals and it is committed to raising the profile of arthritis and making a real difference to people’s lives.
Arthritis Research UK receives no government funding and relies on the generosity and commitment of its supporters to continue funding this world-class research and creating the knowledge which changes the lives of people with arthritis.
University of Birmingham
Birmingham has been challenging and developing great minds for more than a century. Characterised by a tradition of innovation, research at the University has broken new ground, pushed forward the boundaries of knowledge and made an impact on people’s lives.
It continues this tradition today and has ambitions for a future that will embed its work and recognition of the Birmingham name on the international stage.
Universities are never complete. They develop as new challenges and opportunities occur. Birmingham innovates, pushing the frontiers of understanding; asking new research questions, and turning theory through experiment into practice.
University of Glasgow
Founded in 1451, the University of Glasgow is the fourth oldest university in the English-speaking world. It is a broad-based, research intensive institution, a member of the prestigious Russell Group of leading UK research universities, and is striving to change the world with its expertise. Annual earnings for research are £181m, which means that it can make important discoveries, whether that’s finding a way to detect malaria in minutes, or contributing to the biggest particle physics experiment in the world: the Large Hadron Collider.
It knows it cannot succeed alone, which is why it works with partners and friends in Glasgow, Scotland and beyond. Whether it’s sharing expertise on climate change and disease prevention in developing countries, or offering investment to kickstart new collaborations with growing companies in Scotland, the benefits of Glasgow’s ever-expanding network of friendships and partnerships are wide-ranging and reciprocal.
Our vision is of Newcastle as a civic university with a global reputation for academic excellence. We wish to be a world-class civic university putting academic excellence to work, making a contribution to civil society. Over the past three years our contribution to civic engagement has blossomed through the successful launch of three selected Societal Challenge Themes. These are global challenges, particularly relevant in our own city and region, for which we have the academic expertise to contribute towards significant and lasting solutions.
In doing so we are acting out our mission statement, which is
- to be a world-class research-intensive university
- to deliver teaching and facilitate learning of the highest quality
- to play a leading role in the economic, social and cultural development of the North East of England