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.