1. Summary of programme area and objectives

1.1 Infection and inflammation can have devastating effects on vision. The aim of this research programme is to:

· determine how tissue damage occurs from T-cell infiltration in ocular inflammation
· devise novel methods by which this damage can be limited and vision therefore protected
· use molecular biology techniques to aid in the diagnosis of infective agents affecting the eye where current techniques have low detection rates
· run clinical trials to determine whether new treatments are effective in affected patients.
· evaluate the role of vitrectomy surgery in the management of uveitic disease

  2. Programme plan

2.1 In patients with intraocular infection, sampling of cells from within the inflamed eye and stimulation of these cells in vitro, has identified individual T-cell cytokine staining, using fluorescent labelled antibodies which are detected and quantified by the Fluorescent Activated Cell Sorter (FACS). The clinical profile of the disease is correlated with these results with a view to determining which patients are going to do well and preserve vision and which will lose it in the future. Identification of those who will do badly will enable more aggressive treatment to be initiated earlier. In patients on immunosuppressive drugs such as steroids and cyclosporin, the effects of these drugs on the functions of the patients blood T-cells is being looked at to see if therapy can be more closely tailored to the individual patient's requirements rather than the blood levels, which do not correlate well with the therapeutic response.

2.2 In HIV/AIDS patients, the susceptibility to infections which affect the eye such as with cytomegalovirus (CMV) varies with the response to the antiviral therapy the patient is taking and how well their immune function is being restored. Investigations are underway to see if the function and number of CMV specific cells in the patients blood correlates with their protection form CMV.

2.3 PCR techniques have also been applied to the detection of lymphoma cells within the eye since in the older patient, malignancy can masquerade as inflammation, making the true diagnosis difficult to determine. This is a major contributing factor to the poor prognosis of intraocular lymphoma as the real diagnosis is made very late.

2.4 A device that can detect the presence of bacterial or fungal DNA is being developed to allow easy and early differentiation of infection from inflammation. This will also determine the species and allow early initiation of appropriate therapy. The readout system for the results are gel based at the moment and therefore require laboratory facilities but new colourimetric systems to allow office readout are being developed.

2.5 Continuation of the current areas of work as described above are planned. In addition, two new areas are being developed. For patients with ocular inflammation, we aim to identify the genetic basis of disease type, complications and response to treatment. With their informed consent, large numbers of patients are being accurately phenotyped and their response to therapy and surgery categorised. Blood samples have been stored for future genetic analysis for disease susceptibility genes and the large number of genes involved in immune function and the ocular structures attacked by the inflammation. This will allow a greater understanding of why some people respond well to treatment and preserve vision whereas others get lots of complications and suffer severe visual loss.

2.6 In patients with intraocular infection, we are further developing the PCR techniques to allow prediction of antibiotic sensitivity which is not available at the moment when no organism is cultured. It will also allow assessment of whether antibiotic resistance is an increasing problem in ophthalmic infections, and therefore the poor prognosis of intraocular infection, as it is in systemic infections.

2.7 There are several other cytokine-producing cells likely to play an important immunoregulatory role, including extraocular muscle-derived fibroblasts, retinal endothelial cells, conjunctival mast cells, eosinophils and dendritic cells and we will investigate the role(s) of these cells in the future. Immunotherapeutic strategies in chronic ocular inflammatory disease can be applied once we have a better understanding of the role of T cells, tissue-resident cells and the relevant cytokines in each of the chronic ocular diseases.

  3. Future development work in the programme during 2002/3

3.1.1 The research priority in this area is to devise novel therapeutic strategies which are more effective at controlling the inflammation and thereby preventing visual loss. A greater understanding of the disease mechanisms can be achieved by examination of the cells that infiltrate the eye and are present in the ocular fluids. This may identify a cytokine profile produced by the cells which results in aggressive disease and switching these off may be achieved by using other down-regulatory cytokines. In some types of retinal infection, implants containing the therapeutic agent are inserted into the eye and deliver the drug constantly over 6 months. To be able to treat eye inflammation inside the eye has many advantages in that it is likely to be more effective as reliable drug levels are achieved where the drug is needed and all the systemic side effects are avoided.

3.2 New immuno-suppressive drugs can be assessed against current therapy in clinical trials. Many patients are young and healthy apart from their chronic eye problem and therefore it is of major importance that the side effect profile is acceptable for long term treatment. Drugs that could induce disease remission, as has been suggested for interferon alpha, and/or could considerably reduce or replace the need for cortico-steroids, which are the mainstay of treatment, would be ideal.

3.3 Patients with the same clinical phenotype of disease can have very different responses to treatment and visual outcome. Although few types of intraocular inflammation have a strong HLA association, there must be other genetic factors that determine disease out come. This maybe genes that control levels of cytokine production or other immune signals or genes which control processes that metabolise drugs or a myriad of other processes which are involved. By dissecting out these parameters in carefully phenotyped patients, it may be possible to identify patients who will do badly and lose vision. The aim then would be to target these patents for earlier more aggressive treatment to try and prevent this from occurring.

3.4 Small scale series over the years have reported a beneficial effect of vitrectomy in the management of various forms of uveitis. No large scale series has yet reported on this and again the potential exists within the UK to co-ordinate a large scale investigation on the role of vitrectomy surgery in the management of uveitic disease.