Study into the potentially therapeutic immunomodulatory effects of gp120 in autoimmune rheumatic disease

This project focuses on two devastating diseases called Rheumatoid Arthritis (RA) and Systemic Lupus Erythematous (SLE). These are autoimmune diseases where instead of the immune system only fighting infection, it becomes over activated and causes inflammation which is damaging to the body. In RA this mainly affects the lining of the joints, whereas in SLE it can affect lots of parts of the body including the joints, the skin, the lungs, kidney and brain. These diseases can be life-threatening but treatment so far has focused on dampening down the immune system to control and limit the damage caused by the inflammation. These treatments often have side effects, particularly leading to severe infections, or do not work in all people. As medical science progresses we learn more about what causes these diseases and so we can focus on developing so-called targeted treatments to stop them.

Not all immune diseases cause inflammation however. In Human Immunodeficiency Virus (HIV) infection the virus can change the immune system's balance towards an anti-inflammatory state. Although this helps HIV spread, it can also teach us lessons and suggest ideas to suppress the immune system in a targeted way.

HIV has a protein on its surface called gp120, and it is this protein that interacts with elements of the immune system, leading to targeted suppression. Taken away from the virus and by itself this protein is not infective and is not dangerous. However, research shows that gp120 by itself has a number of interesting effects that together decrease immune activation and dampen down inflammation.

In inflammation, cells can produce products called cytokines that drive the cycle of inflammation further. One such example is interferon-alpha (IFNa) which is mainly produced by a cell subtype called plasmacytoid dendritic cells (pDCs). IFNa has been shown to be damaging in RA and in SLE. Interestingly however, gp120 can reduce pDCs from making these damaging inflammatory cytokines, including IFNa. In pDCs gp120 can also increase levels of an enzyme called IDO. This is an important enzyme as it works to reduce inflammation. It does this by both increasing the number of anti-inflammatory immune cells and also reducing the number of inflammatory immune cells. Finally pDCs that have been treated with gp120 can affect other cells (B-cells) to reduce the levels of autoantibodies in the blood. Autoantibodies are markers of autoimmune disease and are seen in RA and SLE.

In this project I want to find out more about what part pDCs play in RA and SLE disease. I also want to see if gp120 can help to reduce any damaging actions of pDCs in these diseases. If this worked, gp120 could be developed as a new treatment for RA and SLE.

I will research this by firstly looking at what the gp120 does on pDCs and other cell types taken from the blood of healthy volunteers. I will next see what happens when using blood from patients with RA and SLE. In patients with RA I will also look at pDCs taken from synovial fluid and synovium (this is the lining of the joint and the fluid that surrounds it) which becomes damaged in RA.

By carrying out the above research I believe that I can 1) start to answer the question if gp120 can be developed as a new treatment for RA and SLE as well as 2) add to the knowledge about what role pDCs have in RA and SLE.

Rheumatoid arthritis (RA) and Systemic Lupus Erythematous (SLE) are autoimmune diseases that result in systemic inflammation and are often associated with autoantibodies. Human Immunodeficiency Virus (HIV) while classically causing a fall in CD4+ T-cell number, can also promote immunomodulatory effects, presumably evolved to help the virus evade immune recognition. Recent advances demonstrate that gp120, an HIV envelope protein, induces indoleamine dioxygenase (IDO) (along with concurrent TLR7 stimulation) and inhibits TLR9 signalling in plasmacytoid dendritic cells (pDCs). In addition gp120 treated pDCs can reduce B-cell activation and antibody production. Finally following binding to CD4, gp120 can also cross-link CD303, a cell surface marker uniquely found on pDCs, and upon binding reduces type 1 interferon production.
These effects have relevance to autoimmune disease. pDCs are prolific IFNa producers and there are suggestions that they are important in RA/SLE although their full role in disease pathogenesis has not been elucidated. IDO is an enzyme important in the catabolism of tryptophan which promotes regulatory T-cell (Treg) generation as well as inhibiting Th17 proliferation and there is an increasing appreciation that TLR9 signalling, a part of the innate immune system, is important in driving autoimmunity in SLE and RA. For example TLR9 stimulation in pDCs increases autoantibody production in B-cells from SLE patients, and many naturally occurring TLR9 ligands in RA synovitis have been identified. Finally symptoms of SLE and RA appear to improve in the initial stages of HIV infection, although may become worse following anti-retroviral therapy and immune reconstitution.
In this project I aim to examine further the role of pDCs in RA and SLE as well as investigating the potential of gp120 as novel immunomodulator for RA /SLE where gp120 i) induces IDO, ii) inhibits inflammatory cytokine production and iii) modulates B-cell autoantibody production.

Translational research is aimed at primarily improving patient care and the main beneficiary of this research will be patients with RA or SLE. There is a significant morbidity associated with RA and SLE, for example in RA the disease exerts a 15-20% reduction in life span from diagnosis. Treatment has relied on immunosuppression however these treatments are often poorly tolerated. Problems include side effects, lack of efficacy and there is the emerging problem of antibodies against biological therapies themselves limiting efficacy. As such, any new progress in understanding disease pathogenesis or drug development is highly attractive. Thus a new therapy, such as gp120, which is in itself poorly immunogenic, would be of primary benefit to the RA/SLE patient populations and potentially other populations of autoimmune disease, i.e. Sjogrens syndrome.

There may also be benefit to other patient groups. In transplantation many of the molecular effects that gp120 may induce, i.e. expansion of regulatory T cell populations, are also desirable and may promote "tolerance" of the transplanted organ. However this therapeutic aspect is beyond the scope of this proposed fellowship but could be explored at a later date.

Poor disease control results in severe morbidity and since RA and SLE commonly present in the working age population this often results in time off work. I anticipate that another therapeutic option available for a population who may have refractory disease to conventional therapy may overall result in less deformity, morbidity and thus allow patients to stay at work. This would reduce the negative burden of these conditions on the UK economy.

As I am investigating the development of a new therapeutic option, there are obviously links to the pharmaceutical industry. There are five million people with rheumatoid arthritis in the main pharmaceutical markets and in 2008 the global sales of arthritis drugs was $35 billion. The development of a new and mechanistically novel therapy would have benefits to the UK economy by supporting this industry.

Newcastle University already has a strong background in dendritic cell physiology and immunotherapy. This project would allow me to further consolidate Newcastle University's reputation of novel dendritic cell based immunotherapy and would also allow research into another dendritic cell subset, i.e. plasmacytoid dendritic cells. Furthermore Newcastle University has been a member of the Athena Swan Charter for many years (the Institute of Cellular Medicine is a recipient of the Silver Award) and is fully committed to recognising and supporting the advancement of womens' careers in science. Thus as a woman in science, this MRC fellowship would also have a positive impact on the overall inclusion and support of women scientists.

In addition a successful award of this fellowship would also have an impact on my career. It would provide me with the training and opportunity to continue in my work in Academic Rheumatology. It would also allow me to explore both the role of plasmacytoid dendritic cells in RA and the therapeutic effects of gp120 in SLE and RA. This would allow me to develop a clear research direction and niche for my future career