Experimental approaches to specific immunotherapies in autoimmune disease: future treatment of endogenous posterior uveitis?

(Auto)immune mediated diseases are diverse and may affect almost any organ. In the past their treatment has been largely with non-specific immunosuppression and supported, in controlling pain, with analgesics and nonsteroidal anti-inflammatory agents in, for example, rheumatoid arthritis. The side effects of immunosuppression with steroids and cytotoxic agents, which for any control of disease have to be taken on a long term basis, often outweigh the benefits of any treatment. However, over the past two decades the discovery of more specific immunosuppressive agents for example, cyclosporin A (CsA), and the further understanding of underlying immune processes (for example, T cell activation, T cell receptors, cytokines) has led to a wave of interest in developing specific treatments for immune mediated diseases. Newer immunosuppressive therapies are aiming to give long term suppression of (auto)immune responses with only short term treatment and specificity for the desired antigen. Endogenous posterior uveoretinitis (EPU) is one of the best ocular examples of putative (auto)immune disease. However, there is still conflict as to what constitutes EPU. EPU is characterised by a combination of discrete clinical signs which include vitreal infiltration with inflammatory cells (vitritis), focal or diffuse chorioretinal infiltration with leucocytes (choroiditis), inner and outer retinal vessel inflammation (retinal vasculitis), and macular and optic nerve head oedema. 1 2 From these building blocks of signs arises a large spectrum of clinical conditions including sympathetic ophthalmia, intermediate uveitis, birdshot chorioretinitis, and pigment epithelitis. Although these conditions vary in their presentation, degree of HLA association, and response to relatively non-specific treatment, there is growing evidence both clinically and in experimental models that these conditions are characterised by an exaggerated immune response which causes tissue destruction and, without an obvious infective aetiology, is likely to be autoimmune in nature (Table 1). 3 4 The immune mechanisms generated are either directed towards autoantigens or as a response triggered, for example, by an infectious agent (that is, foreign antigen), which may show some homology with host antigens and generate cross reactivity (molecular mimicry). The points at which the inflammatory response may be inhibited successfully would depend on whether the immune response was directed against host or foreign antigen which enters the tissue. Either way, when no overt infectious or neoplastic aetiology is found treatment may be directed towards dampening the resulting inflammatory cascade and hopefully reduce tissue damage. With the former I will discuss the possibility of inhibiting specific autoreactive T cells as opposed to inhibiting inflammatory mediators (cytokines) which result as a consequence of a pathogenic immune response. Although present treatment is successful in some cases of EPU, as well as other autoimmune conditions, it is restricted by the required long term use, resistance in some patients, and significant side effects. Therefore there is a strong need for more selective and specific immunotherapy which is rapidly being developed and is now entering the era of clinical trials. This review concentrates on both current advances and future aspects of suppressing the (auto)immune response in EPU with examples of immunosuppressive treatments of other autoimmune diseases and experimental models of autoimmune disease including experimental autoimmune uveoretinitis (EAU), the animal model of EPU.